Radicicol derivatives

ABSTRACT

Radicicol derivatives represented by the following formula (I) having tyrosine kinase inhibition activity or pharmacologically acceptable salts thereof:  
                 
 
     wherein R 1  and R 2  are the same or different, and each represents hydrogen, alkanoyl, alkenoyl, tert-butyldiphenylsilyl or tert-butyldimethylsilyl; R 3  represents Y—R 5  {wherein Y represents substituted or unsubstituted alkylene; and R 5  represents CONR 6 R 7  (wherein R 6  represents hydrogen, hydroxyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted higher alkyl, and the like; R 7  represents hydroxyl, substituted lower alkyl, and the like), CO 2 R 12  (wherein R 12  represents substituted lower alkyl, substituted or unsubstituted higher alkyl, and the like), and the like} and the like; X represents halogen or is combined together with R 4  to represent a single bond; and R 4  is combined together with X to represent a single bond, or represents hydrogen, alkanoyl, and the like.

TECHNICAL FIELD

[0001] The present invention relates to novel radicicol derivatives orpharmacologically acceptable salts thereof which show tyrosine kinaseinhibition activity and have antitumor or immunosuppression effects.

BACKGROUND ART

[0002] It is known that microbial metabolite radicicol represented bythe following formula (B) has an antifungal effect and an anticancereffect [Nature, 171, 344 (1953); Neoplasma, 24, 21 (1977)], animmunosuppression effect (Japanese Published Unexamined PatentApplication No. 298764/94), or morphology normalization effect of ras ormos canceration cells [Oncogene, 11, 161 (1995)].

[0003] Furthermore, it is known that radicicol derivatives in which thephenolic hydroxyl group is modified with various acyl groups have anantitumor effect (Japanese Published Unexamined Patent Application No.226991/92). In addition, it is disclosed that radicicol derivatives inwhich the phenolic hydroxyl group is modified with an acyl group or analkyl group show an angiogenesis inhibition effect (Japanese PublishedUnexamined Patent Application No. 279279/94) or an interleukin 1production inhibition effect (Japanese Published Unexamined PatentApplication No. 40893/96). Recently, oxime derivatives of dienone of aradicicol derivative showing antitumor action and immunosuppressionaction have been published (WO 96/33989: published on Oct. 31, 1996),and antitumor radicicol derivatives represented by the following formula(B′) have also been published (Japanese Published Unexamined PatentApplication 202781/97: published on Aug. 5, 1997).

[0004] (In the formula, R^(1p) and R^(2p) represent a hydrogen atom oran acyl group; and X^(o) represents a halogen atom, a hydroxyl group ora lower alkoxy group.)

[0005] Additionally, it is known that ansamycins antibiotics,geldanamycin, represented by formula (C) [The Journal of Antibiotics,23, 442 (1970)] has tyrosine kinase inhibition activity and antitumoreffects [for example, Cancer Research, 52, 1721 (1992) and CancerResearch, 54, 2724 (1994)]. It is shown that these effects are expressedby the inhibition of the activation of a tyrosine kinase, such as Src,ErbB-2, Lck or the like, and a serine/threonine kinase Raf-1, throughthe formation of a complex of geldanamycin with a molecular chaperoneHsp (heat shock/stress protein) 90 by binding to Hsp90 [for example,Proceedings of the National Academy of Sciences of the U.S.A, 91, 8324(1994) and The Journal of Biological Chemistry, 270, 24585 (1995)].Consequently, drugs capable of acting upon Hsp90 are also included intyrosine kinase inhibitors and useful not only as antitumor agents butalso for the prevention and treatment of various diseases such asosteoporosis, immune diseases, and the like.

[0006] Tyrosine kinase is an enzyme which uses ATP as a phosphate donorand catalyzes transfer of its γ-phosphate group to the hydroxyl group ofa specified tyrosine residue of a substrate protein, thereby taking animportant role in the control mechanism of intracellular signaltransduction. Various tyrosine kinase families are known. Tyrosinekinase activities, such as Src in colon cancer, ErbB-2 in breast cancerand gastric cancer, Abl in leukemia, and the like, increase. Disorderedincrease in the tyrosine kinase activity causes abnormal differentiationand proliferation of cells. Consequently, specific inhibitors oftyrosine kinase are useful in preventing and treating various diseases,including as antitumor agents.

[0007] Lck is a tyrosine kinase which is activated when T lymphocytesare activated by antigen stimulation, and an inhibitor of this enzyme isuseful as an immunosuppressant. Also, it is known that Src relates tobone resorption in osteoclast, and an inhibitor of this tyrosine kinaseis useful as a bone resorption inhibitor for the treatment ofosteoporosis. Additionally, inhibitors of receptor type tyrosine kinasesof various growth factors, such as EGF-R (epidermal growth factorreceptor), FGF-R (fibroblast growth factor receptor), PDGF-R(platelet-derived growth factor receptor), and the like, are useful as asolid cancer growth inhibitor, an angiogenesis inhibitor, a vascularsmooth muscle growth inhibitor, and the like.

DISCLOSURE OF THE INVENTION

[0008] An object of the present invention is to provide novel radicicolderivatives or pharmacologically acceptable salts thereof which showtyrosine kinase inhibition activity and have antitumor orimmunosuppression effects.

[0009] The present invention can provide radicicol derivativesrepresented by the following formula (I) or pharmacologically acceptablesalts thereof:

[0010] wherein R¹ and R² are the same or different, and each representshydrogen, alkanoyl, alkenoyl, tert-butyldiphenylsilyl ortert-butyldimethylsilyl;

[0011] R³ represents:

[0012] Y—R⁵ {wherein Y represents substituted or unsubstituted alkylene;and R⁵ represents CONR⁶R⁷ (wherein R⁶ represents hydrogen, hydroxyl,substituted or unsubstituted lower alkyl, substituted or unsubstitutedhigher alkyl, substituted or unsubstituted lower cycloalkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted lower alkoxy,substituted or unsubstituted aryl, a substituted or unsubstitutedheterocyclic group, or NR⁸R⁹ (wherein R⁸ and R⁹ are the same ordifferent, and each represents hydrogen, substituted or unsubstitutedlower alkyl, substituted or unsubstituted higher alkyl, substituted orunsubstituted lower cycloalkyl, substituted or unsubstituted aryl, asubstituted or unsubstituted heterocyclic group, substituted orunsubstituted alkanoyl, substituted or unsubstituted aroyl, carbonylbound to a substituted or unsubstituted heterocyclic ring, orsubstituted or unsubstituted arylcarbamoyl), or is combined togetherwith R⁷ and adjoining N to represent a substituted or unsubstitutedheterocyclic group; and R⁷ is combined together with R⁶ and adjoining Nto represent a substituted or unsubstituted heterocyclic group, orrepresents hydroxyl, substituted lower alkyl, substituted orunsubstituted higher alkyl, substituted or unsubstituted lowercycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted lower alkoxy, substituted or unsubstituted aryl, asubstituted or unsubstituted heterocyclic group, or NR¹⁰R¹¹ (wherein R¹⁰and R¹¹ have the same meaning as R⁸ and R⁹ defined above,respectively)), CO₂R¹²R (wherein R¹² represents substituted lower alkyl,substituted or unsubstituted higher alkyl, substituted or unsubstitutedlower cycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, or a substituted or unsubstituted heterocyclicgroup), substituted or unsubstituted aryl, substituted or unsubstitutedpyridyl, substituted or unsubstituted pyridonyl, substituted orunsubstituted pyrrolidonyl, substituted or unsubstituted uracilyl,substituted or unsubstituted piperidyl, substituted or unsubstitutedpiperidino, substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted morpholino, substituted or unsubstituted morpholinyl,substituted or unsubstituted piperazinyl, substituted or unsubstitutedthiomorpholino, or substituted or unsubstituted dioxolanyl},

[0013] COR¹³ (wherein R¹³ represents hydrogen, substituted orunsubstituted lower alkyl, substituted or unsubstituted higher alkyl,substituted or unsubstituted aryl, substituted or unsubstituted loweralkoxy, or NR¹⁴R¹⁵ (wherein R¹⁴ and R¹⁵ are the same or different, andeach represents hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted higher alkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted pyridyl, or R¹⁴ and R¹⁵ arecombined together with adjoining N to represent a substituted orunsubstituted heterocyclic group)), or

[0014] substituted or unsubstituted aryl;

[0015] X represents halogen, or is combined together with R⁴ torepresent a single bond; and

[0016] R⁴ is combined together with X to represent a single bond, orrepresents hydrogen, alkanoyl, alkenoyl, or —SO-Z {wherein Z representsformula (A):

[0017] wherein R^(1A) and R^(2A) have the same meaning as R¹ and R²defined above, respectively; X^(A) represents halogen; and W representsO or N—O—R^(3A) (wherein R^(3A) has the same meaning as R³ definedabove)}.

[0018] Hereinafter, the compound represented by formula (I) will becalled compound (I). Compounds of other formula numbers with also becalled in the same manner.

[0019] (1) Explanation of Each Group

[0020] In the definition of each group of compound (I), the term “lower”means 1 to 8 carbon atoms, and the term “higher” means 9 to 30 carbonatoms, unless otherwise indicated.

[0021] Examples of the alkanoyl include straight or branched groupshaving 1 to 30 carbon atoms, such as formyl, acetyl, propanoyl,isopropanoyl, butanoyl, caproyl, lauroyl, myristoyl, palmitoyl,stearoyl, and the like. Examples of the alkenoyl include straight orbranched groups having 3 to 30 carbon atoms, such as acryloyl,methacryloyl, crotonoyl, isocrotonoyl, palmitoleoyl, linoleoyl,linolenoyl, and the like. Examples of the alkyl moiety of the loweralkyl and the lower alkoxy include straight or branched groups, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,isooctyl, and the like, and one of the carbon atoms thereof may besubstituted with a silicon atom. Examples of the higher alkyl includestraight or branched groups, such as decanyl, dodecyl, hexadecyl, andthe like. Examples of the alkenyl include straight or branched groupshaving 2 to 30 carbon atoms, such as vinyl, allyl, 1-propenyl,2-butenyl, 1-pentenyl, 2-hexenyl, 1,3-pentadienyl, 1,3-hexadienyl,dodecenyl, hexadecenyl, and the like. Examples of the lower cycloalkylinclude groups having 3 to 8 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like. Examplesof the aryl include phenyl, naphthyl, and the like, and the aryl moietyof aroyl and arylcarbamoyl has the same meaning. Examples of theheterocyclic group include alicyclic heterocyclic groups, aromaticheterocyclic groups, and the like, such as pyridonyl, pyrrolidonyl,uracilyl, dioxolanyl, pyrrolyl, tetrazolyl, pyrrolidinyl, thienyl,morpholino, thiomorpholino, piperazinyl, pyrazolidinyl, piperidino,pyridyl, homopiperazinyl, pyrazolyl, pyrazinyl, indolyl, isoindolyl,furyl, piperidyl, quinolyl, phthalazinyl, imidazolidinyl, imidazolinyl,pyrimidinyl, and the like. The heterocyclic group moiety in the carbonylbound to a heterocyclic ring has the same meaning as defined above, andexamples of the entire group containing carbonyl include furoyl,thenoyl, nicotinoyl, isonicotinoyl, and the like. Examples of thenitrogen containing heterocyclic group formed by R⁶ and R⁷ with theadjoining N and the nitrogen containing heterocyclic group formed by R¹⁴and R¹⁵ with the adjoining N (said heterocyclic group may furthercontain O, S or other N) include pyrrolidyl, morpholino, thiomorpholino,piperazinyl, pyrazolidinyl, pyrazolinyl, piperidino, homopiperazinyl,indolinyl, isoindolinyl, perhydroazepinyl, perhydroazocinyl, indolyl,isoindolyl, and the like. Examples of the alkylene include those groupsin which one hydrogen atom is removed from the group of alkyl moiety ofthe above lower alkyl or higher alkyl. Examples of the halogen includefluorine, chlorine, bromine and iodine atoms.

[0022] (2) Explanation of Substituent in Each Group

[0023] Examples of the substituent in the substituted lower alkyl, thesubstituted higher alkyl, the substituted alkenyl, the substituted loweralkoxy and the substituted alkanoyl include 1 to 3 substituents, whichare the same or different, such as hydroxyl, lower cycloalkyl, lowercycloalkenyl, lower alkoxy, lower alkanoyloxy, azido, amino, mono- ordi-lower alkylamino, mono- or di-lower alkanoylamino, loweralkoxycarbonylamino, lower alkenyloxycarbonylamino, halogen, loweralkanoyl, substituted or unsubstituted aryl, a substituted orunsubstituted heterocyclic group, cyclic imido (a group formed byremoving hydrogen bound to an imido N atom), CONR¹⁶R¹⁷ (wherein R¹⁶ andR¹⁷ are the same or different, and each represents hydrogen, hydroxyl,lower alkyl, lower cycloalkyl, higher alkyl, alkenyl, lower alkoxy,aryl, a heterocyclic group, or NR¹⁸R¹⁹ (wherein R¹⁸ and R¹⁹ are the sameor different, and each represents hydrogen, lower alkyl, lowercycloalkyl, aryl, a heterocyclic group, lower alkanoyl, aroyl, carbonylbound to a heterocyclic ring, or arylcarbamoyl)), CO₂R²⁰ (wherein R²⁰represents hydrogen, lower alkyl, higher alkyl, lower cycloalkyl,alkenyl, substituted or unsubstituted aryl, or a substituted orunsubstituted heterocyclic group), or —(OCH₂CH₂)_(n)OCH₃ (wherein n isan integer of 1 to 10).

[0024] Examples of the substituent in the substituted alkylene include 1to 3 substituents, which are the same or different, such as hydroxyl,lower alkoxy, lower alkanoyloxy, azido, amino, mono- or di-loweralkylamino, mono- or di-lower alkanoylamino, lower alkoxycarbonylamino,lower alkenyloxycarbonylamino, halogen, lower alkanoyl, substituted orunsubstituted aryl, substituted or unsubstituted pyridyl, substituted orunsubstituted pyridonyl, substituted or unsubstituted pyrrolidonyl,substituted or unsubstituted uracilyl, substituted or unsubstitutedpiperidyl, substituted or unsubstituted piperidino, substituted orunsubstituted pyrrolidinyl, substituted or unsubstituted morpholino,substituted or unsubstituted morpholinyl, substituted or unsubstitutedpiperazinyl, substituted or unsubstituted thiomorpholino, substituted orunsubstituted dioxolanyl, cyclic imido (a group formed by removinghydrogen bound to an imido N atom), CONR¹⁶R¹⁷ (wherein R¹⁶ and R¹⁷ havethe same meaning as defined above), or CO₂R²⁰ (wherein R²⁰ has the samemeaning as defined above).

[0025] Examples of the substituent in the substituted lower cycloalkyl,the substituted aryl, the substituted heterocyclic group, thesubstituted aroyl, the carbonyl bound to a substituted heterocyclicring, the substituted arylcarbamoyl, the substituted pyridyl, thesubstituted pyridonyl, the substituted pyrrolidonyl, the substituteduracilyl, the substituted piperidyl, the substituted piperidino, thesubstituted pyrrolidinyl, the substituted morpholino, the substitutedmorpholinyl, the substituted piperazino, the substituted piperazinyl,the substituted thiomorpholino, the substituted dioxolanyl and thesubstituted nitrogen containing heterocyclic group formed with theadjoining N include 1 to 3 substituents, which are the same ordifferent, such as hydroxyl, lower alkyl, lower alkyl substituted with aheterocyclic ring (said heterocyclic ring may be substituted with loweralkyl), higher alkyl, alkenyl, lower cycloalkyl, lower cycloalkenyl,lower alkoxy, lower alkoxy-lower alkoxy, lower alkanoyloxy, azido,amino, mono- or di-lower alkylamino, mono- or di-lower alkanoylamino,lower alkoxycarbonylamino, lower alkenyloxycarbonylamino, halogen, loweralkanoyl, aryl, a heterocyclic group, cyclic imido (a group formed byremoving hydrogen bound to an imido N atom), CONR¹⁶R¹⁷ (wherein R¹⁶ andR¹⁷ have the same meaning as defined above), CO₂R²⁰ (wherein R²⁰ has thesame meaning as defined above), or SO₂NR²¹R²² (wherein R²¹ and R²² arethe same or different, and each represents hydrogen or lower alkyl). Thelower alkyl, the higher alkyl, the alkenyl, the lower cycloalkyl, thelower alkoxy, the halogen, the aryl, the aroyl, the arylcarbamoyl, theheterocyclic group, and the carbonyl bound to a heterocyclic ring usedherein have the same meaning as defined above. The lower alkyl moietiesof the mono- or di-lower alkylamino, the lower alkoxycarbonyl, the loweralkoxycarbonylamino, and the lower alkoxy-lower alkoxy have the samemeaning as defined above. The lower alkenyl moiety of the loweralkenyloxycarbonylamino means the above alkenyl group having 2 to 8carbon atoms, such as vinyl, allyl, 1-propenyl, 2-butenyl, 1-pentenyl,2-hexenyl, 1,3-pentadienyl, 1,3-hexadienyl, and the like. Examples ofthe lower cycloalkenyl include those having 4 to 8 carbon atoms, such as2-cyclopentenyl, 2-cyclohexenyl, 1,3-cyclopentadienyl, and the like.Examples of the lower alkanoyl moiety of the lower alkanoyl, the loweralkanoyloxy and the mono- or di-lower alkanoylamino include straight orbranched groups having 1 to 8 carbon atoms, such as formyl, acetyl,propanoyl, isopropanoyl, butanoyl, caproyl, and the like. Examples ofthe cyclic imido include phthalimido, succinimido, glutarimido, and thelike.

[0026] As compound (I), compounds in which X is a halogen are preferred,and compounds in which X is combined together with R⁴ to represent asingle bond are also preferred. Among the compounds in which X iscombined together with R⁴ to represent a single bond, compounds in whichR¹ and R² are hydrogen are preferred. Among these, compounds in which R³(wherein R³ has the same meaning as defined above) is Y—R⁵ (wherein R⁵has the same meaning as defined above) are more preferred. Among thecompounds in which X is combined together with R⁴ to represent a singlebond, compounds in which R¹ and R² are hydrogen, R³ is Y—R⁵ (wherein R⁵has the same meaning as defined above) and R⁵ is substituted orunsubstituted aryl, and the like, are most preferred, and among these,compounds in which R⁵ is pyrrolidonyl are particularly preferred.

[0027] The pharmacologically acceptable salts of compound (I) includeacid addition salts, metal salts, ammonium salts, organic amine additionsalts, amino acid addition salts, and the like. Examples of the acidaddition salts include inorganic acid salts (for example, hydrochloride,hydrobromide, sulfate, phosphate, and the like), and organic acid salts(for example, formate, acetate, oxalate, benzoate, methanesulfonate,p-toluenesulfonate, maleate, fumarate, tartrate, citrate, succinate,lactate, and the like). Examples of the metal salts include alkali metalsalts (for example, lithium salt, sodium salt, potassium salt, and thelike), alkaline earth metal salts (for example, magnesium salt, calciumsalt, and the like), aluminum salts, zinc salts, and the like. Examplesof the ammonium salts include salts with ammonium, tetramethylammonium,and the like. Examples of the organic amine addition salts includeaddition salts with morpholine,.piperidine, and the like. Examples ofthe amino acid addition salts include addition salts with glycine,phenylalanine, aspartic acid, glutamic acid, lysine, and the like.

[0028] The compound of the present invention is generally prepared usingradicicol as a starting material. Compound (I) may contain variousstereoisomers, geometric isomers, tautomeric isomers, and the like. Allof possible isomers and their mixtures are included in the presentinvention, and the mixing ratio is not particularly limited.

[0029] A production method of compound (I) is described below.

[0030] The production method of compound (I) mainly comprises oximeformation (production method 1),acylation/carbamoylation/alkoxycarbonylation (production method 2),alkylation (production method 3), amidation/esterification (productionmethod 4), desilylation (production method 5), halohydrination(production method 6), silylation (production method 7), and acylation(production method 8), and each compound of interest is produced bycombining these reaction steps depending on the object.

[0031] In the production methods shown below, when a defined groupchanges under conditions of the employed method or is not fit forcarrying out the method, the compound of interest can be prepared usingan introduction-elimination method of protecting groups usually used insynthetic organic chemistry [for example, see Protective Groups inOrganic Synthesis, T. W. Greene, John Wiley & Sons Inc. (1981)]. Asoccasion demands, the sequence of reaction steps, such as introductionof substituent groups and the like, may be changed.

[0032] Production Method 1

[0033] Compound (Ia) can be prepared according to following reactionstep, by oxime formation of the dienone carbonyl of radicicol, compound(D) which is prepared from radicicol by a known method (JapanesePublished Unexamined Patent Application No. 226991/92) or compound (E)which is prepared from radicicol or a radicicol derivative in which oneof the phenolic hydroxyl groups is substituted with alkanoyl or alkenoylin accordance with a known method [for example, Journal of the AmericanChemical Society, 94, 6190 (1972)).

[0034] [In the above reaction formula, R^(1a) and R^(2a) representgroups in which tert-butyldimethylsilyl and tert-butyldiphenylsilyl areremoved from R¹ and R² described above; R^(1b) and R^(2b) representgroups in which at least one of R¹ and R² described above is substitutedwith tert-butyldimethylsilyl or tert-butyldiphenylsilyl; R^(3a) is agroup in which COR¹³ (wherein R¹³ has the same meaning as describedabove) is removed from R³ described above; and R¹ and R² have the samemeaning as defined above.]

[0035] Step 1

[0036] Compound (Ia) can be prepared by allowing compound (D) orcompound (E) to react with compound (II) represented by the followingformula H₂N—O—R^(3a) (II) (wherein R^(3a) has the same meaning asdefined above) or an acid addition salt thereof.

[0037] Examples of the reaction solvent include pyridine, chloroform,dichloromethane, ethyl acetate, ether, tetrahydrofuran (THF),dimethylformamide (DMF), acetonitrile, and the like, which may be usedeither alone or as a mixture thereof, and pyridine is preferred.Examples of the acid include hydrochloric acid, acetic acid,trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid,camphorsulfonic acid, and the like, and they are preferably used in anamount of 0.1 to 10 equivalents based on compound (D) or (E). When anacid addition salt of compound (II) is used, the reaction can be carriedout in the presence of a base, for example, amines (e.g., pyridine,triethylamine, diisopropylethylamine, N,N-dimethylaniline,N,N-diethylaniline, or the like) or alkali metal carbonate orbicarbonate (e.g., sodium carbonate, potassium carbonate, or the like),in an amount of 1 equivalent or more based on the acid addition salt ofcompound (II), preferably using pyridine which also serves as thesolvent. The compound (II) or an acid addition salt thereof is used inan amount of 1 equivalent or more, preferably 1 to 5 equivalents, basedon compound (D) or (E). The reaction is carried out at a temperature of−20 to 100° C., preferably 20 to 60° C., and the reaction completesafter 1 to 80 hours.

[0038] Production Method 2

[0039] Compound (Ib) can be prepared by the steps in which compound (F)is converted into oxime compound (G), and then the resulting hydroxylgroup is subjected to acylation, carbamoylation or alkoxycarbonylation.

[0040] [In the above reaction formula, R^(1c) and R^(2c) are the same ordifferent, and each represents alkanoyl, alkenoyl,tert-butyldimethylsilyl or tert-butyldiphenylsilyl, and R^(3b)represents COR¹³ (wherein R¹³ has the same meaning as defined above).]

[0041] Step 2-1

[0042] Compound (G) can be prepared by allowing compound (F) to reactwith hydroxylamine or an acid addition salt thereof according to methodof the above step 1.

[0043] Step 2-2

[0044] Compound (Ib) can be prepared by allowing compound (G) to reactwith compound (III) represented by the following formula R¹³COCl (III)(wherein R¹³ has the same meaning as defined above), or with compound(IV) represented by the following formula R²³NCO (IV) (wherein R²³represents substituted or unsubstituted lower alkyl, substituted orunsubstituted higher alkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted pyridyl), in the presence of a base.

[0045] As the reaction solvent, dichloromethane, ether, THF, DMF, andthe like, may be used alone or as a mixture thereof. As the base, amines(for example, pyridine, triethylamine, diisopropylethylamine, or thelike) are used in an amount of 0.1 equivalent or more, preferably 1 to10 equivalents, based on compound (III) or (IV). Compound (III) or (IV)is used in an amount of 1 equivalent or more, preferably 1 to 5equivalents, based on compound (G). The reaction is carried out at atemperature of −80 to 100° C., preferably −80 to 0° C., when compound(III) is used, or at a temperature of 0 to 80° C. when compound (IV) isused, and each reaction completes after 10 minutes to 48 hours.

[0046] Production Method 3

[0047] Compound (Ic) can be prepared by a step in which the hydroxylgroup of the above compound (G) is alkylated.

[0048] [In the above reaction formula, R^(3c) represents Y—R⁵ (wherein Yand R⁵ have the same meaning as defined above), and R^(1c) and R^(2c)have the same meaning as defined above.]

[0049] Step 3

[0050] Compound (Ic) can be prepared by allowing compound (G) to reactwith compound (V) represented by the following formula HOR²⁴ (V)(wherein R²⁴ has the same meaning as R^(3c) defined above) in thepresence of a condensing agent.

[0051] As the reaction solvent, toluene, THF, dichloromethane, and thelike, are used alone or as a mixture thereof. As the condensing agent,trivalent phosphorous compounds (for example, triphenylphosphine,tributylphosphine, or the like) and azo compounds (for example, diethylazodicarboxylate (DEAD), 1,1-(azodicarbonyl) dipiperidine, and the like)are used as a mixture thereof. Each of compound (V) and the condensingagent is used in an amount of 1 equivalent or more, preferably 1 to 5equivalents, based on compound (G). The reaction is carried out at atemperature of −20 to 80° C., preferably 0 to 30° C., and the reactioncompletes after 5 minutes to 48 hours.

[0052] Production Method 4

[0053] Compound (Id) can be prepared by steps in which compound (H) isconverted into oxime compound (J) in which a carboxyl group isintroduced, and then the carboxyl group is subjected to amidation oresterification.

[0054] {In the above reaction formula, R^(3d) represents Y—R^(5a)[wherein R^(5a) represents CONR⁶R⁷ (wherein R⁶ and R⁷ have the samemeaning as defined above) or CO₂R¹² (wherein R¹² has the same meaning asdefined above), and Y has the same meaning as defined above], and Y, R¹and R² have the same meaning as defined above.}

[0055] Step 4-1

[0056] Compound (J) can be prepared by allowing compound (H) to reactwith compound (VI) represented by the following formula H₂N—O—Y—CO₂H(VI) (wherein Y has the same meaning as defined above) or an acidaddition salt thereof according to the method of the above step 1.

[0057] Step 4-2

[0058] Compound (Id) can be prepared by allowing compound (J) to reactwith compound (VII) represented by the following formula HNR⁶R⁷ (VII)(wherein R⁶ and R⁷ have the same meaning as defined above) or an acidaddition salt thereof, or with a compound (VIII) represented by thefollowing formula HOR¹² (VIII) (wherein R¹² has the same meaning asdefined above), in the presence of a condensing agent.

[0059] As the condensing agent,1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDCI),N,N′-dicyclohexylcarbodiimide (DCC), 1,1′-carbonyldiimidazole, or thelike, is used. Additionally, the reaction can be accelerated by addingan additive agent, such as N-hydroxysucciniimide (HONSu),4-(dimethylamino)pyridine (DMAP), 1-hydroxybenzotriazole hydrate (HOBt),or the like, in an amount of 0.1 to 5 equivalents based on compound (J).As the reaction solvent, dichloromethane, ether, THF, DMF, and the like,may be used alone or as a mixture thereof. When an acid addition salt ofcompound (VII) is used, the reaction can be carried out in the presenceof a base, such as amines (for example, pyridine, triethylamine,diisopropylethylamine, or the like), preferably triethylamine, in anamount of 1 equivalent or more, preferably 1 to 10 equivalents, based onthe acid addition salt of compound (VII). Each of compound (VII) or anacid addition salt thereof or compound (VIII) and the condensing agentis used in an amount of 1 equivalent or more, preferably 1 to 5equivalents, based on compound (J). The reaction is carried out at atemperature of −20 to 80° C., preferably 0 to 40° C., and each reactioncompletes after 10 minutes to 48 hours.

[0060] Production Method 5

[0061] Compound (If) can be prepared by carrying out desilylation ofcompound (Ie) which is a derivative compound of (I) in which at leastone of R¹ and R² is substituted with tert-butyldimethylsilyl ortert-butyldiphenylsilyl.

[0062] (In the above reaction formula, R^(1b), R^(2b) and R³ have thesame meaning as defined above, and R^(1d) and R^(2d) are groups in whichat least one of tert-butyldimethylsilyl or tert-butyldiphenylsilyl ofthe above R^(1b) and R^(2b) is substituted with hydrogen.)

[0063] Step 5

[0064] Compound (If) can be prepared by allowing compound (Ie) to reactwith a desilylation agent.

[0065] As the reaction solvent, THF, chloroform, dichloromethane,toluene, water, methanol, and the like may be used alone or as a mixturethereof. Examples of the desilylation agent include tetrabutylammoniumfluoride (TBAF), sodium fluoride, hydrofluoric acid, and the like. Thereaction may be carried out by increasing the reaction pH by adding anacid, such as acetic acid, hydrochloric acid or the like. Thedesilylation agent is used in an amount of 0.1 equivalent or more,preferably 1 to 10 equivalents, based on compound (Ie). The reaction iscarried out at a temperature of −20 to 50° C., and the reactioncompletes after 5 minutes to 24 hours.

[0066] Production method 6

[0067] Compound (Ih) can be prepared by ring-opening the epoxide ofcompound (Ig) into a halohydrin or the like.

[0068] [In the above reaction formula, R^(1a), R^(2a) and R³ have thesame meaning as defined above; X^(a) represets halogen; and R^(4a)represents hydrogen, formyl, or —SO-Z (wherein Z has the same meaning asdefined above).]

[0069] Step 6-1

[0070] A member of compound (Ih) in which R^(4a) is hydrogen can beprepared by allowing compound (Ig) to react with an acid (for example,hydrogen chloride, hydrogen bromide, or the like) or a Lewis acid (forexample, titanium tetrachloride, or the like).

[0071] As the solvent, dioxane, THF, ether, chloroform, dichloromethane,DMF, acetonitrile, methanol, ethyl acetate, and the like may be usedeither alone or as a mixture thereof. The acid or Lewis acid is used inan amount of 1 equivalent or more, preferably 1 to 10 equivalents, basedon compound (Ig). The reaction is carried out at a temperature of −20 to40° C., preferably 0 to 40° C., and the reaction completes after 10minutes to 48 hours.

[0072] Step 6-2

[0073] A member of compound (Ih) in which R^(4a) is formyl can beprepared by allowing compound (Ig) to react with phosphorous oxychlorideor phosphorous oxybromide in DMF. Phosphorous oxychloride or phosphorousoxybromide is used in an amount of 1 equivalent or more, preferably 2 to5 equivalents, based on compound (Ig). The reaction is carried out at atemperature of −10 to 40° C., preferably 0 to 40° C., and the reactioncompletes after 1 to 48 hours.

[0074] Step 6-3

[0075] A dimer compound as a member of compound (Ih) in which R^(4a) is—SO-Z (wherein Z has the same meaning as defined above) can be preparedby allowing compound (Ig) to react with thionyl chloride or thionylbromide. As the solvent, DMF, chloroform, dichloromethane, dimethylsulfoxide (DMSO), acetonitrile, and the like may be used either alone oras a mixture thereof. Thionyl chloride or thionyl bromide is used in anamount of 1 equivalent or more, preferably 2 to 10 equivalents, based oncompound (Ig). The reaction is carried out at a temperature of −10 to40° C., preferably 0 to 40° C., and the reaction completes after 1 to 48hours.

[0076] Production Method 7

[0077] Compound (Ij) which is a derivative of compound (I) in which atleast one of R¹ and R² is substituted with tert-butyldimethylsilyl ortert-butyldiphenylsilyl can be prepared from compound (Ii) by thefollowing step.

[0078] (In the above reaction formula, R³, R⁴, and X have the samemeaning as defined above; R^(1e) and R^(2e) represent both hydrogen, orone represents hydrogen and the other represents alkanoyl or alkenoyl;and R^(1f) and R^(2f) represent groups in which at least one hydrogen ofeither of the above R^(1e) and R^(2e) is substituted withtert-butyldimethylsilyl or tert-butyldiphenylsilyl.)

[0079] Step 7

[0080] Compound (Ij) can be prepared by allowing compound (Ii) to reactwith tert-butyl(chloro)dimethylsilane or tert-butylchlorodiphenylsilanein the presence of a base.

[0081] As the solvent, chloroform, dichloromethane, ether, THF, acetone,DMF, acetonitrile, and the like are used either alone or a mixturethereof. As the base, amines (for example, pyridine, imidazole,triethylamine, diisopropylethylamine, or the like) are used.Tert-butyl(chloro)dimethylsilane or tert-butylchlorodiphenylsilane isused in an amount of 1 equivalent or more, preferably 1 to 10equivalents, based on compound (Ii). The base is used in an amount of 1equivalent or more, preferably 1 to 10 equivalent, based ontert-butyl(chloro)dimethylsilane or tert-butylchlorodiphenylsilane. Thereaction is carried out at a temperature of −20 to 50° C., preferably 10to 40° C., and the reaction completes after 10 minutes to 24 hours.

[0082] Production Method 8

[0083] Compound (Im) in which at least one hydrogen of any one of R¹, R²and R⁴ in compound (I) is substituted with alkanoyl or alkenoyl can beprepared by carrying out acylation of the following compound (Ik).

[0084] (In the above reaction formula, R³ and X have the same meaning asdefined above; at least one of R^(1g), R^(2g) and R^(4b) representshydrogen; and R^(1h), R^(2h) and R^(4c) represent groups in which atleast one hydrogen of the above R^(1g), R^(2g) and R^(4b) is substitutedwith alkanoyl or alkenoyl.)

[0085] Step 8

[0086] Compound (Im) can be prepared by allowing compound (Ik) to reactwith 1 equivalent or more, preferably 1 to 100 equivalents, of an acidhalide, an acid anhydride, a mixed acid anhydride containing thealkanoyl or alkenoyl of interest, or the like, in the presence of abase.

[0087] As the solvent, DMF, DMSO, chloroform, dichloromethane, toluene,and the like may be used either alone or as a mixture thereof. Anoptional hydroxyl group can be modified by optionally carrying outintroduction and elimination of a protecting group of the hydroxylgroup, and it is possible to modify a plurality of hydroxyl groups atthe same time. As the base, pyridine, triethylamine,N,N-dimethylaniline, N,N-diethylaniline, or the like is used in anamount of 1 equivalent or more, preferably 1 to 200 equivalents, basedon compound (Ik). It is possible to use a base (for example, pyridine,or the like) also as the solvent. Additionally, the reaction can beaccelerated by adding DMAP or the like in an amount of 0.1 to 4equivalents based on compound (Ik). The reaction is carried out at atemperature of −20 to 50° C., and the reaction completes after 5 minutesto 24 hours.

[0088] In the production of compound (I), conversion of the functionalgroup of R¹, R², R³, R⁴ or X can be carried out not only by the abovesteps but also by known methods [for example, Comprehensive OrganicTransformations, R. C. Larock (1989)].

[0089] Isolation and purification of the products of the above methodscan be carried out by carrying out optional combinations of techniquesgenerally used in organic syntheses (e.g., filtration, extraction,washing, drying, concentration, crystallization, various types ofchromatography, and the like). The intermediates may be used in thesubsequent reactions without purification.

[0090] If a salt of compound (I) is prepared, the salt of compound (I)can be purified as such when it can be prepared; or, when the compoundis prepared in its free form, its salt can be formed by dissolving orsuspending it in an appropriate solvent and adding an acid or basethereto.

[0091] Also, compound (I) or pharmacologically acceptable salts thereofmay exist in the form of addition products with water or varioussolvents, and these addition products are also included in the presentinvention. Examples of compound (I) are shown in Table 1. TABLE 1Specific examples of compound (I)

Compound R³ 1

2

3

4

5 CH₂CONH(CH₂)₂N(CH₂CH₃)₂ 6 CH₂CONH(CH₂)₂OH 7 CH₂CON[(CH₂)₂OH]₂ 8CH₂CONHCH₂CO₂CH₃ 9 CH₂CONHNH₂ 10 CH₂CONHNHCONHC₆H₅ 11

12

13

14

15

16 CH₂CONH(CH₂)₉CH₃ 17

18

19

20

21

22

23

24

25

26

27

28 CH₂CONHC₆H₅ 29

30

31

32

33 CH₂CONHN(CH₃)₂ 34

35 CH₂CONHNHC₅H₆ 36

37

38

39

40

41 CH₂CO₂(CH₂CH₂O)₅CH₃ 42 CH₂CO₂(CH₂CH₂O)₃CH₃ 43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73 CO₂CH₂CH₃ 74 CONHCH₃ 75 COCH₃ 76 C₆H₅

[0092] Next, pharmacological activities of typical examples of compound(I) are described by the following test examples.

TEST EXAMPLE 1

[0093] Inhibition Test of Intracellular Tyrosine Kinase:

[0094] SR-3Y1 cells were cultured at 37° C. for 15 hours in anatmosphere of 5% carbon dioxide, using Dulbecco's modified Eagle'smedium (DMEM) containing 10% fetal calf serum (FCS), to which eachradicicol derivative to be tested had been added in variedconcentration. The thus cultured cells were lysed at 4° C. for 20minutes in a cooled buffer for lysis use (50 mM Tris HCl, pH 7.5, 150 mMsodium chloride (NaCl), 1% Triton X-100, 0.1% sodium dodecyl sulfate(SDS), 1% sodium deoxycholate, 2 mM ethylenediaminetetraacetic acid(EDTA), 1 mM phenylmethanesulfonyl fluoride (PMSF), 20 μM leupeptin,0.15 unit/ml aprotinin, 1 mM sodium orthovanadate (Na₃VO₄) and thencentrifuged at 20,000 G for 30 minutes. After measuring proteinconcentration in the resulting supernatant fluid, samples were adjustedto the same protein quantity per lane to carry out separation of proteinby SDS-PAGE. The thus separated protein samples were transferred onto anitrocellulose membrane to which were subsequently added a mousepolyclonal phosphotyrosine antibody MX-pTYR (Kyowa Medex Co., Ltd.) as afirst antibody and a horseradish peroxidase-conjugated mouse IgGantibody (BIO-RAD Co.) as a second antibody, thereby reacting them withthe protein samples on the membrane. Detection was carried out using ECLreagent (Amersham Co.), and the amount of tyrosine-phosphorylatedprotein was determined by scanning the density of bands prepared on anX-ray film. The activity of radicicol derivatives to inhibit tyrosinephosphorylation can be shown as a concentration (IC₅₀) of eachderivative by which the ratio of tyrosine-phosphorylated protein isreduced to half in comparison with a control to which the drug is notadded.

[0095] The results are shown in Table 2. TABLE 2 Inhibitory activity ofintracellular tyrosine kinase Compound IC₅₀ (μM) Radicicol 0.37  1 0.02 3 0.21 73 0.13

[0096] According to Table 2, the test compounds show clearly strongeraction to inhibit intracellular tyrosine kinase activity than radicicol,and therefore, compound (I) is useful as a tyrosine kinase inhibitor.

TEST EXAMPLE 2

[0097] Inhibition Test on the Growth of Rat Normal Fibroblast Cell Line3Y1-B and its v-src Oncogene Transformed Cell Line SR-3Y1:

[0098] The cells were inoculated into a 96 well microplate (# 167008,manufactured by Nunc) in an amount of 1,000 cells per well andpre-cultured at 37° C. for 24 hours in a 5% carbon dioxide gas incubatorusing Dulbecco's modified Eagle's medium (DMEM) which had beensupplemented with 10% fetal calf serum (FCS). Next, a DMSO solution ofeach test compound which had been adjusted to 10 mM was serially dilutedwith the culturing medium and added to the wells in 50 ml portions.Thereafter, the culturing was continued at 37° C. for 72 hours in the 5%carbon dioxide gas incubator. Five hours before completion of theculturing, 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide(manufactured by Sigma, hereinafter referred to as “MTT”) which had beendissolved in the culturing medium to a final concentration of 1 mg/mlwas dispensed into the wells in 50 ml portions. After completion of theculturing, DMSO was dispensed into the wells in 150 ml portions, and theplate was vigorously stirred using a plate mixer to dissolveMTT-formazan crystals completely. Thereafter, absorbance at 550 nM wasmeasured using a microplate reader MTP-32 (manufactured by CoronaDenki). The cell growth inhibition activity was expressed by 50%inhibition concentration (IC₅₀).

[0099] The results are shown in Table 3. TABLE 3 Growth inhibitionactivity upon rat normal fibroblast cell line 3Y1-B and its v-srconcogene transformed cell line SR-3Y1 Growth inhibition activity IC₅₀(μM) Compond 3Y1-B SR-3Y1 Radicicol 0.780 0.042  1 0.008 <0.004 21 0.0320.018 27 0.041 0.010 44 0.069 0.012 50 0.120 0.021 53 0.008 <0.004 550.009 <0.004 67 0.140 0.018 69 0.008 0.004 72 0.055 0.010 74 0.072 0.02776 0.110 0.026

[0100] According to Table 3, the test compounds showed stronger cellgrowth inhibition activity upon SR-3Y1 than that upon 3Y1-B and strongercell growth inhibition activity than that of radicicol upon SR-3Y1.Because of these results, compound (I) is useful as an antitumor agent.

TEST EXAMPLE 3

[0101] Antitumor Test on Nude Mouse-Transplanted Human Breast CancerMX-1 Solid Tumor:

[0102] From a tumor lump of a-human breast cancer cell line MX-1subcultured in nude mice (BALB/c nu/nu mice: CLEA Japan), a portionshowing good growth was selected and cut into a 2 mm square fragmentwhich was then transplanted under the abdominal side skin of each malenude mouse of 7 to 9 weeks of age using a trocar. The tumor size wasmeasured on the 13th day after the tumor transplantation to selectproperly growing tumors having a tumor volume of 100 to 300 mm³(calculated by a calculation formula of “major axis×minor axis²×{fraction (1/2)}”), the mice were optionally grouped into 5 animals pergroup, and then each test compound which had been dissolved in a 7.5%cremohor EL (manufactured by Sigma)/5% dimethylacetamide (DMA)/87.5%physiological saline solution was administered to the mice byintravenous injection at a dosage of 0.05 ml (100 mg/kg) per day, once aday for 5 days. The antitumor activity of each test compound wasexpressed by a ratio (T/C) of the tumor volume (T) in the testdrug-administered group to the tumor volume (C) in the control group onthe 12th or 14th day after administration of the test compound.

[0103] The results are shown in Table 4. TABLE 4 Antitumor activityagainst human breast cancer MX-1 solid tumor inoculated in nude mouseDay measured (after Compound T/C (%) administration of test compound) 13 14 51 33 14 53 46 12 69 4 12

[0104] According to Table 4, the test compounds show excellent antitumoractivity, and therefore, compound (I) is useful as an antitumor agent.

TEST EXAMPLE 4

[0105] Effect of Decreasing Intracellular Raf-1 Protein Quantity andErk2 Phosphorylation Inhibition Activity:

[0106] Activated K-ras gene-introduced rat kidney epithelial cell lineKNRK 5.2 was cultured at 37° C. for 40 hours in an atmosphere of 5%carbon dioxide gas using Dulbecco's modified Eagle's medium (DMEM) whichwas supplemented with 10% fetal calf serum (FCS) and to which was addedeach radicicol derivative at respective test concentration. Theresulting cells were lysed for 30 minutes at 4° C. in a cooled bufferfor lysis use [50 mM HEPES NaOH, pH 7.4, 250 mM sodium chloride (NaCl),1 mM ethylenediaminetetraacetic acid (EDTA), 1% Nonidet P-40 (NP40), 1mM dithiothreitol (DTT), 1 mM phenylmethylsulfonyl fluoride (PMSF), 5μg/ml leupeptin, 2 mM sodium orthovanadate (Na₃VO₄), 1 mM sodiumfluoride (NaF), 10 mM β-glycerophosphatel and then centrifuged at 30,000G for 10 minutes. The protein content of the thus prepared supernatantfluids was measured to prepare samples having the same protein quantityfor each lane, and then separation of proteins was carried out bySDS-PAGE. The thus separated protein samples were transferred on apolyvinylidene difluoride (PVDF) membrane, and then anti-phosphorylationMAPK antibody (anti-phospho MAPK, manufactured by New England Biolabs),anti-Erk2 antibody (anti-Erk2, manufactured by Upstate Biotechnology)and anti-Raf-1 antibody (anti-Raf-1(C-12), manufactured by Santa CruzBiotechnology) were added thereto as primary antibodies and allowed toreact with the proteins on the membrane. Thereafter, a horseradishperoxidase-labeled secondary antibody (anti-rabbit Ig antibody oranti-mouse Ig antibody, manufactured by Amersham) capable of reactingwith respective primary antibodies was added thereto as the secondaryantibody to carry out the reaction. Detection was carried out using ECLreagent (manufactured by Amersham), and the amount of phosphorylatedErk2 protein, total Erk2 protein and Raf-1 protein was determined bycarrying out density scanning of the bands generated on the X-ray film.The Erk2 phosphorylation inhibition activity of radicicol derivatives isdetermined by calculating the ratio of phosphorylated Erk2 protein(phosphorylated Erk2 protein/total Erk2 protein) based on the resultsprepared from the samples of respective drug concentrations, which isexpressed as the concentration of each derivative (IC₅₀) by which theratio becomes half in comparison with the case in which the drug is notadded. Also, the Raf-1 protein decreasing action is examined bycalculating the ratio of Raf protein to the amount of Erk2 protein whichdoes not cause changes in the protein quantity by the drug-treatment(Raf-1 protein/total Erk2 protein) based on the results prepared fromthe samples having respective drug concentrations, which is expressed asthe concentration of each derivative (IC₅₀) by which the ratio becomeshalf in comparison with the case in which the drug is not added.

[0107] The results are shown in Table 5. TABLE 5 Effect of decreasingintracellular Raf-1 protein quantity and Erk2 phosphorylation inhibitionactivity Raf-1 protein quantity Erk2 phosphorylation Compound decrease:IC₅₀ (μM) inhibition: IC₅₀ (μM) 50 0.34 0.35 53 0.38 0.07 64 0.19 0.1169 0.12 0.06

[0108] According to Table 5, the test compounds showed effect ofdecreasing intracellular Raf-1 protein quantity and Erk2 phosphorylationinhibition activity.

[0109] Compound (I) or a pharmacologically acceptable salt thereof isadministered orally or parenterally as it is or in the form of apharmaceutical composition. Examples of the dosage form of such apharmaceutical composition include tablets, pills, powders, granules,capsules, suppositories, injections, drip infusions, and the like.

[0110] These dosage forms can be prepared by employing generally knownmethods and may contain various fillers, lubricants, binders,disintegrators, suspending agents, tonicity agents, emulsifying agents,absorption enhancers, and the like.

[0111] Examples of carriers to be used in the pharmaceutical compositioninclude water, distilled water for injection use, physiological saline,glucose, fructose, sucrose, mannitol, lactose, starch, corn starch,cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropylcellulose, alginic acid, talc, sodium citrate, calcium carbonate,calcium hydrogenphosphate, magnesium stearate, urea, silicone resin,sorbitan fatty acid ester, glycerol fatty acid ester and the like, whichmay be optionally selected according to the kind of the pharmaceuticalpreparation.

[0112] Although the dosage and the number of administration times forthe purposes may vary depending on the intended therapeutic effect,administration method, treating period, age, body weight, and the like,it may be administered generally in a dose of 0.01 to 5 mg/kg per dayper adult.

BEST MODE OF CARRYING OUT THE INVENTION

[0113] Examples and Reference Examples are shown below. The NMR datashown in Examples and Reference Examples are values obtained bymeasuring at 270 MHz, and the number of protons observed, multiplicityand coupling constant (unit, Hz) are shown in that order in parenthesesafter the 8 value of each signal.

[0114] TBS and Boc shown in the following structural formulae and Tablesmean tert-butyldimethylsilyl and tert-butoxycarbonyl, respectively.

EXAMPLE 1

[0115] Compound 1:

[0116] (1-1):

[0117] A 1.50 g (4.11 mmol) portion of radicicol was dissolved in 5 mlof pyridine, and the solution was mixed with 1.00 g (9.15 mmol) ofaminooxyacetic acid hemihydrochloride and stirred at room temperaturefor 20 hours and then at 60° C. for 1.5 hours. The solvent wasevaporated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (chloroform/methanol=49/1)to obtain 692 mg (yield, 38%) of a compound (K). The thus preparedcompound (K) was found to be a mixture of oxime-based isomers (about3:1) according to ¹H-NMR.

[0118] FAB-MS m/z: 438 [M+H]⁺

[0119] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.27 (1H, dd, 16.1, 11.2Hz), 6.82 (1H, d, 16.1 Hz), 6.42 (1H, s), 6.17 (1H, dd, 11.2, 10.5 Hz),5.61 (1H, dd, 10.5, 3.4 Hz), 5.31 (1H, m), 4.64 (2H, m), 3.91 (1H, d,16.4 Hz), 3.82 (1H, d, 16.4 Hz), 3.34 (1H, m), 3.02 (1H, m), 2.42 (1H,m), 1.60 (1H, ddd, 14.4, 9.0, 4.2 Hz), 1.53 (3H, d, 6.6 Hz).

[0120] (1-2):

[0121] A 230 mg (0.525 mmol) portion of compound (K) was dissolved in 3ml of DMF, and the solution was mixed with 121 mg (0.788 mmol) of HOBt,151 mg (0.788 mmol) of EDCI and 0.078 ml (0.788 mmol) of piperidine andstirred at room temperature for 23 hours and 40 minutes. The reactionsolution was mixed with a 0.01 M phosphate buffer of pH 7 and thenextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine and dried with anhydrous sodium sulfate, and then thesolvent was evaporated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (chloroform/methanol=50/1)to obtain 63.6 mg (yield, 24%) of compound 1. The thus prepared compound1 was found to be a mixture of oxime-based isomers (about 4:1) accordingto ¹H-NMR.

[0122] FAB-MS m/z: 505 [M+H]⁺

[0123] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.27 (1H, dd, 15.8, 10.9Hz), 6.80 (1H, d, 16.3 Hz), 6.44 (1H, s), 6.17 (1H, dd, 11.9, 10.9 Hz),5.61 (1H, dd, 10.9, 3.5 Hz), 5.31 (1H, m), 4.80 (2H, s), 3.93 (1H, d,15.9 Hz), 3.82 (1H, d, 16.3 Hz), 3.40-3.60 (4H, m), 3.34 (1H, m), 3.02(1H, m), 2.49 (1H, ddd, 14.4, 3.5, 3.5 Hz), 1.60-1.80 (7H, m), 1.52 (3H,d, 6.4 Hz).

EXAMPLE 2

[0124] Compound 2:

[0125] According to (1-2) described in Example 1, 109 mg (yield, 49%) ofcompound 2 was prepared from 200 mg (0.457 mmol) of compound (K), 77 mg(0.503 mmol) of HOBt, 96 mg (0.503 mmol) of EDCI and 0.042 ml (0.503mmol) of pyrroridine. The thus prepared compound 2 was found to be amixture of oxime-based isomers (about 3:1) according to ¹H-NMR.

[0126] FAB-MS m/z: 491 [M+H]⁺

[0127] Major component: ¹H-NMR (DMSO-d₆) δ (ppm): 10.34 (1H, br s),10.00 (1H, br s), 7. 14 (1H, dd, 16.0, 11.4 Hz), 6,74 (1H, d, 15.8 Hz),6.51 (1H, s), 6.23 (1H, dd, 11.2, 10.9 Hz), 5.63 (1H, dd, 10.4, 3.5 Hz),5.14 (1H, m), 4.68 (2H, s), 3.80 (1H, d, 15.8 Hz), 3.51 (1H, d, 15.2Hz), 3.27-3.54 (4H, m), 3.05 (1H, m), 2.44 (1H, m), 1.70-1.91 (5H, m),1.43 (3H, d, 6.3 Hz).

EXAMPLE 3

[0128] Compound 3:

[0129] According to (1-2) described in Example 1, 42 mg (yield, 12%) ofcompound 3 was prepared from 300 mg (0.685 mmol) of compound (K), 155 mg(0.753 mmol) of DCC, 87 mg (0.753 mmol) of HONSu and 0.090 ml (0.753mmol) of morpholine. The thus prepared compound 3 was found to be amixture of oxime-based isomers (about 4:1) according to ¹H-NMR.

[0130] FAB-MS m/z: 507 [M+H]⁺

[0131] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.28 (1H, dd, 15.8, 11.4Hz), 6.78 (1H, d, 16.3 Hz), 6.42 (1H, s), 6.17 (1H, dd, 11.4, 10.4 Hz),5.62 (1H, dd, 10.4, 3.0 Hz), 5.30 (1H, m), 4.82 (2H, s), 3.87 (1H, d,15.8 Hz), 3.82 (1H, d, 16.3 Hz), 3.57-3.71 (8H, m), 3.34 (1H, m), 3.05(1H, m), 2.42 (1H, ddd, 14.4, 4.0, 3.5 Hz), 1.94 (1H, m), 1.52 (3H, d,6.9 Hz).

EXAMPLE 4

[0132] Compound 4:

[0133] According to (1-2) described in Example 1, 24 mg (yield, 20%) ofcompound 4 was prepared from 100 mg (0.288 mmol) of compound (K), 52 mg(0.251 mmol) of DCC, 29 mg (0.251 mmol) of HONSu and 0.028 ml (0.251mmol) of 1-methylpiperazine. The thus prepared compound 4 was found tobe a mixture of oxime-based isomers (about 4:1) according to ¹H-NMR.

[0134] FAB-MS m/z: 520 [M+H]⁺

[0135] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.01 (1H, dd, 15.8, 11.4Hz), 6.69 (1H, d, 15.8 Hz), 6.33 (1H, s), 6.07 (1H, t, 10.9 Hz), 5.52(1H, dd, 10.4, 4.0 Hz), 5.20 (1H, m), 4.72 (2H, s), 3.84 (1H, d, 16.3Hz), 3.72 (1H, d, 16.3 Hz), 3.41-3.55 (4H, m), 3.25 (1H, m), 2.92 (1H,m), 2.28-2.41 (5H, m), 2.22 (3H, s), 1.50 (1H, m), 1.42 (3H, d, 6.4 Hz).

EXAMPLE 5

[0136] Compound 5:

[0137] According to (1-2) described in Example 1, 46 mg (yield, 37%) ofcompound 5 was prepared from 100 mg (0.288 mmol) of compound (K), 52 mg(0.251 mmol) of DCC, 29 mg (0.251 mmol) of HONSu and 0.035 ml (0.251mmol) of N,N-diethylethylenediamine. The thus prepared compound 5 wasfound to be a mixture of oxime-based isomers (about 3:1) according to¹H-NMR.

[0138] FAB-MS m/z: 537 [M+H]⁺

[0139] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.30 (1H, dd, 15.8, 11.4Hz), 6.84 (1H, d, 16.3 Hz), 6.39 (1H, s), 6.18 (1H, t, 10.9 Hz), 5.63(1H, dd, 10.9, 3.5 Hz), 5.30 (1H, m), 3.96 (2H, br), 3.44-3.52 (2H, m),3.36 (1H, m), 3.00 (1H, m), 2.77-2.82 (6H, m), 2.60 (1H, m), 1.67 (1H,m), 1.51 (3H, d, 6.4 Hz), 1.07-1.19 (6H, m).

EXAMPLE 6

[0140] Compound 6:

[0141] According to (1-2) described in Example 1, 87 mg (yield, 40%) ofcompound 6 was prepared from 200 mg (0.456 mmol) of compound (K), 88 mg(0.457 mmol) of EDCI, 56 mg (0.457 mmol) of DMAP and 25 mg (0.457 mmol)of 2-aminoethanol. The thus prepared compound 6 was found to be amixture of oxime-based isomers (about 5:1) according to ¹H-NMR.

[0142] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.30 (1H, dd, 15.8, 11.4Hz), 6.85 (1H, d, 16.3 Hz), 6.44 (1H, s), 6.19 (1H, t, 10.9 Hz), 5.63(1H, dd, 10.9, 3.0 Hz), 5.31 (1H, m), 4.58 (2H, s), 3.96 (1H, d, 16.3Hz), 3.85 (1H, d, 16.3 Hz), 3.54-3.70 (2H, m), 3.31-3.40 (2H, m), 3.31(1H, m), 3.02 (1H, m), 2.43 (1H, m), 1.61 (1H, m), 1.52 (3H, d, 6.4 Hz).

EXAMPLE 7

[0143] Compound 7:

[0144] According to (1-2) described in Example 1, 45 mg (yield, 13%) ofcompound 7 was prepared from 300 mg (0.685 mmol) of compound (K), 132 mg(0.685 mmol) of EDCI, 84 mg (0.685 mmol) of DMAP and 97 mg (0.685 mmol)of 2,2′-iminodiethanol hydrochloride. The thus prepared compound 7 wasfound to be a mixture of oxime-based isomers (about 5:1) according to¹H-NMR.

[0145] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.26 (1H, dd, 15.8, 10.9Hz), 6.83 (1H, d, 15.8 Hz), 6.42 (1H, s), 6.17 (1H, dd, 11.4, 10.4 Hz),5.60 (1H, dd, 10.4, 3.5 Hz), 5.29 (1H, m), 4.91 (2H, s), 3.91 (1H, d,15.8 Hz), 3.80 (1H, d, 15.8 Hz), 3.71-3.90 (4H, m), 3.52-3.59 (4H, m),3.34 (1H, m), 3.00 (1H, m), 2.42 (1H, ddd, 14.8, 3.5, 3.5 Hz), 1.60 (1H,m), 1.52 (3H, d, 6.4 Hz).

EXAMPLE 8

[0146] Compound 8:

[0147] According to (1-2) described in Example 1, 89 mg (yield, 38%) ofcompound 8 was prepared from 200 mg (0.456 mmol) of compound (K), 87 mg(0.456 mmol) of EDCI, 56 mg (0.457 mmol) of DMAP and 63 mg (0.502 mmol)of glycine methyl ester hydrochloride. The thus prepared compound 8 wasfound to be a mixture of oxime-based isomers (about 4:1) according to¹H-NMR.

[0148] FAB-MS m/z: 509 [M+H]⁺

[0149] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.30 (1H, dd, 16.3, 11.9Hz), 6.87 (1H, d, 15.8 Hz), 6.44 (1H, s), 6.20 (1H, dd, 10.4, 9.4 Hz),5.63 (1H, dd, 10.4, 4.0 Hz), 5.31 (1H, m), 4.85 (2H, s), 4.02 (1H, d,2.0 Hz), 3.96 (1H, d, 15.8 Hz), 3.83 (1H, d, 15.8 Hz), 3.73 (3H, s),3.36 (1H, m), 3.03 (1H, m), 2.44 (1H, ddd, 14.3, 3.5, 3.5 Hz), 1.65 (1H,m), 1.53 (3H, d, 6.4 Hz).

EXAMPLE 9

[0150] Compound 9:

[0151] A 46 mg (0.150 mmol) portion of compound (K) was dissolved in 1.5ml of tetrahydrofuran, and the solution was mixed with 23 mg (0.200mmol) of HOBt, 2.7 mg (0.022 mmol) of DMAP and 44 mg (0.228 mmol) ofEDCI and stirred at room temperature for 16 hours. The resultingprecipitate was separated by filtration, and the solvent was evaporatedunder reduced pressure. The thus prepared residue was dissolved in 1.5ml of tetrahydrofuran, and the solution was mixed with 0.100 ml (0.720mmol) of triethylamine and 0.050 ml (1.030 mmol) of hydrazine hydrateand stirred at room temperature for 12 hours. The reaction solution wasmixed with ethyl acetate, washed with a saturated ammonium chlorideaqueous solution and dried with anhydrous sodium sulfate, and then thesolvent was evaporated under reduced pressure. The resulting residue waspurified by silica gel column chromatography (chloroform/methanol=24/1)to obtain 33 mg (yield, 48%) of compound 9. The thus prepared compound 9was found to be a mixture of oxime-based isomers (about 3:1) accordingto ¹H-NMR.

[0152] FAB-MS m/z: 452 [M+H]⁺

[0153] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.28 (1H, dd, 16.1, 11.3Hz), 6.83 (1H, d, 16.1 Hz), 6.43 (1H, s), 6.19 (1H, dd, 11.3, 10.7 Hz),5.62 (1H, dd, 10.7, 3.7 Hz), 5.30 (1H, m), 3.94 (1H, d, 16.1 Hz), 3.79(1H, d, 16.1 Hz), 3.31 (1H, m), 3.02 (1H, m), 2.43 (1H, m), 1.59 (1H,m), 1.52 (3H, d, 6.5 Hz).

EXAMPLE 10

[0154] Compound 10:

[0155] According to (1-2) described in Example 1, 35 mg (yield, 27%) ofcompound 10 was prepared from 100 mg (0.228 mmol) of compound (K), 44 mg(0.228 mmol) of EDCI and 35 mg (0.228 mmol) of 4-phenylsemicarbazide.The thus prepared compound 10 was found to be a mixture of oxime-basedisomers (about 5:1) according to ¹H-NMR.

[0156] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.23-7.42 (5H, m), 7.02(1H, t, 7.4 Hz), 6.88 (1H, d, 15.8 Hz), 6.45 (1H, s), 6.18 (1H, t, 10.9Hz), 5.62 (1H, dd, 10.9, 3.5 Hz), 5.31 (1H, m), 4.73 (2H, s), 3.97 (1H,d, 16.3 Hz), 3.86 (1H, d, 16.3 Hz), 3.36 (1H, m), 3.01 (1H, m), 2.42(1H, ddd, 14.3, 3.5, 3.5 Hz), 1.61 (1H, m), 1.51 (3H, d, 6.4 Hz).

EXAMPLES 11-37

[0157] Compounds 11 to 38 were prepared from compound (K) according to(1-2) described in Example 1.

EXAMPLE 11

[0158] Compound 11:

[0159] Isomer ratio: about 10:1

[0160] FAB-MS m/z: 519 [M+H]⁺

[0161] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.78 (1H, br), 7.86(1H, br s), 7.14 (1H, dd, 15.8, 11.6 Hz), 6.75 (1H, d, 15.8 Hz), 6.60(1H, s), 6.09 (1H, dd, 11.6, 10.2 Hz), 5.60 (1H, dd, 10.6, 3.0 Hz), 5.47(1H, m), 4.85 (1H, d, 13.9 Hz), 4.79 (1H, d, 13.9 Hz), 4.69 (1H, br),3.98 (1H, br), 3.37-3.56 (4H, m), 3.16 (1H, br), 2.94 (2H, dd, 8.6, 2.6,2.3 Hz), 2.31 (1H, ddd, 15.2, 3.6, 3.6 Hz), 1.95 (1H, ddd, 15.2, 4.0,4.0 Hz), 1.74 (2H, br), 1.53 (3H, d, 6.9 Hz), 1.49-1.58 (2H, br),1.20-1.29 (4H, br).

EXAMPLE 12

[0162] Compound 12:

[0163] Isomer ratio: about 3:1

[0164] FAB-MS m/z: 519 [M+H]⁺

[0165] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.99 (1H, br), 8.00(1H, br), 7.16 (1H, m), 6.73 (1H, d, 16.2 Hz), 6.59 (1H, s), 6.11 (1H,dd, 10.6, 10.2 Hz), 5.62 (1H, br d, 9.6 Hz), 5.48 (1H, m), 4.80 (2H, s),4.67 (1H, d, 12.2 Hz), 4.54 (2H, br), 4.00 (1H, br), 3.73-3.89 (2H, br),3.17 (1H, br), 3.04 (1H, m), 2.50-2.65 (2H, m), 2.32 (1H, ddd, 15.2,3.6, 3.3 Hz), 1.93 (1H, ddd, 18.8, 4.6, 4.6 Hz), 1.58-1.70 (2H, m), 1.54(3H, d, 6.9 Hz), 1.04-1.19 (2H, m), 0.94 (3H, d, 6.3 Hz).

EXAMPLE 13

[0166] Compound 13:

[0167] Isomer ratio: about 3:1

[0168] FAB-MS m/z: 521 [M+H]⁺

[0169] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.16 (1H, m), 6.70 (1H,d, 16.2 Hz), 6.57 (1H, s), 6.11 (1H, dd, 10.6, 10.2 Hz), 5.63 (1H, br d,11.2 Hz), 5.48 (1H, m), 4.80 (2H, s), 4.63 (1H, br), 3.95 (3H, br), 3.76(1H, br), 3.19-3.47 (3H, m), 2.96 (1H, br), 2.33 (1H, m), 1.90 (1H, m),1.54 (3H, d, 6.6 Hz), 1.20-1.28 (4H, m).

EXAMPLE 14

[0170] Compound 14:

[0171] Isomer ratio: about 8:1

[0172] FAB-MS m/z: 588 [M+H]⁺

[0173] Major component: ¹H-NMR (CDCl₃+CD₃OD) δ (ppm): 7.01 (1H, dd,16.0, 11.0 Hz), 6.62 (1H, d, 15.8 Hz), 6.34 (1H, s), 6.06 (1H, dd, 11.6,9.9 Hz), 5.46 (1H, br d, 10.6 Hz), 5.34 (1H, br), 4.68 (2H, s), 4.55(1H, d, 17.8 Hz), 3.96 (1H, br), 3.20 (1H, br), 2.82-2.99 (2H, m), 2.60(8H, br), 2.25 (1H, br d, 11.6 Hz), 1.89 (2H, br), 1.70-1.80 (4H, br),1.61 (4H, br), 1.44 (3H, d, 6.6 Hz).

EXAMPLE 15

[0174] Compound 15:

[0175] Isomer ratio: about 3:1

[0176] FAB-MS m/z: 548 [M+H]⁺

[0177] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.13 (1H, dd, 16.0, 11.4Hz), 6.64 (1H, d, 16.2 Hz), 6.41 (1H, s), 6.06 (1H, dd, 11.9, 10.2 Hz),5.57 (1H, dd, 10.2, 3.0 Hz), 5.37 (1H, m), 4.70 (2H, s), 4.33-4.52 (2H,m), 3.91-4.01 (2H, m), 3.17 (1H, br), 2.80-3.08 (2H, m), 2.66 (1H, m),2.24-2.40 (2H, m), 1.54-1.84 (5H, br), 1.47 (3H, d, 6.6 Hz).

EXAMPLE 16

[0178] Compound 16:

[0179] Isomer ratio: about 4:1

[0180] FAB-MS m/z: 577 [M+H]⁺

[0181] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.71 (1H, br), 8.83(1H, br), 7.23 (1H, dd, 16.0, 11.4 Hz), 6.66 (1H, d, 16.2 Hz), 6.60 (1H,s), 6.41 (1H, t, 5.8 Hz), 6.13 (1H, dd, 11.2, 10.9 Hz), 5.67 (1H, dd,10.2, 3.0 Hz), 5.47 (1H, m), 4.66 (1H, br), 4.59 (2H, s), 4.02 (1H, d,15.2 Hz), 3.25-3.35 (2H, m), 3.20 (1H, br), 2.95 (1H, m), 2.33 (1H, m),1.95 (1H, m), 1.54 (3H, d, 6.6 Hz), 1.51 (2H, br), 1.21 (14H, br), 0.83(3H, t, 5.6 Hz).

EXAMPLE 17

[0182] Compound 17:

[0183] Isomer ratio: about 13:1

[0184] FB-MS m/z: 513 [M+H]⁺

[0185] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.77 (1H, br), 7.25(1H, dd, 16.2, 11.2 Hz), 7.02 (1H, br), 6.68 (1H, d, 16.2 Hz), 6.61 (1H,s), 6.51 (1H, t, 5.9 Hz), 6.17 (1H, dd. 11.2, 10.6 Hz), 5.71 (1H, dd,10.2, 3.3 Hz), 5.51 (1H, m), 4.73 (1H, d, 15.8 Hz), 4.62 (2H, s), 4.06(1H, d, 15.2 Hz), 3.61 (2H, t, 6.3 Hz), 3.45-3.54 (2H, m), 3.22 (1H,br), 2.99 (1H, ddd, 8.3, 2.6, 2.6 Hz), 2.36 (1H, ddd, 15.2, 3.6, 3.6Hz), 1.95-2.10 (3H, m), 1.58 (3H, d, 6.6 Hz).

EXAMPLE 18

[0186] Compound 18:

[0187] Isomer ratio: about 10:1

[0188] FAB-MS m/z: 509 [M+H]⁺

[0189] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.76 (1B, br), 7.23(1H, dd, 15.5, 10.9 Hz), 6.84 (1H, br), 6.69 (1H, d, 16.2 Hz), 6.67 (1H,br), 6.16 (1H, dd, 11.2, 10.6 Hz), 5.70 (1H, dd, 10.4, 3.1 Hz), 5.51(1H, m), 4.75 (1H, br), 4.64 (2H, s), 4.10 (1H, br), 3.45-3.57 (6H, m),3.22 (1H, br), 2.99 (1H, ddd, 8.3, 2.6, 2.3 Hz), 2.36 (1H, ddd, 15.2,3.6, 3.3 Hz), 2.00 (1H, ddd, 15.2, 4.3, 4.0 Hz), 1.58 (3H, d, 6.6 Hz),1.14 (3H, t, 7.1 Hz).

EXAMPLE 19

[0190] Compound 19:

[0191] Isomer ratio: about 3:1

[0192] FAB-MS m/z: 477 [M+H]⁺

[0193] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.77 (1H, br), 7.47(1H, br), 7.24 (1H, dd, 16.1, 11.2 Hz), 6.68 (1H, d, 16.2 Hz), 6.61 (1H,s), 6.40 (1H, br), 6.16 (1H, dd, 11.6, 11.5 Hz), 5.86 (1H, m), 5.70 (1H,dd, 10.2, 3.3 Hz), 5.51 (1H, m), 5.23 (1H, dd, 17.2, 1.3 Hz), 5.16 (1H,dd, 10.2, 1.3 Hz), 4.71 (1H, br), 4.64 (2H, s), 3.96-3.98 (3H, m), 3.21(1H, br), 2.99 (1H, m), 2.35 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.98 (1H,ddd, 15.2, 4.0, 4.0 Hz), 1.56 (3H, d, 6.9 Hz).

EXAMPLE 20

[0194] Compound 20:

[0195] Isomer ratio: about 4:1

[0196] FAB-MS m/z: 533 [M+H]⁺

[0197] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.75 (1H, br), 8.17(1H, br), 7.24 (1H, dd, 16.2, 11.2 Hz), 6.68 (1H, d, 15.8 Hz), 6.42 (1H,t, 6.1 Hz), 6.16 (1H, dd. 11.2, 10.6 Hz), 5.69 (1H, dd, 10.4, 3.1 Hz),5.50 (1H, m), 4.61 (2H, s), 4.04 (1H, d, 14.2 Hz), 3.09-3.27 (4H, m),2.99 (1H, m), 2.35 (1H, ddd, 15.2, 3.3, 3.3 Hz), 1.98 (1H, m), 1.68-1.73(6H, br), 1.56 (3H, d, 6.6 Hz), 1.49 (1H, br), 1.10-1.24 (4H, br).

EXAMPLE 21

[0198] Compound 21:

[0199] Isomer ratio: about 7:1

[0200] FAB-MS m/z: 617 [M+H]⁺

[0201] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.71 (1H, br), 7.75(1H, br), 7.20 (1H, dd, 16.0, 11.4 Hz), 6.64 (1H, d, 15.8 Hz), 6.54 (1H,s), 6.52-6.64 (3H, m), 6.11 (1H, dd, 11.5, 10.2 Hz), 5.67 (1H, dd, 10.2,3.3 Hz), 5.46 (1H, m), 4.69 (1H, d, 13.5 Hz), 4.63 (1H, d, 16.2 Hz),4.62 (1H, br), 4.45 (1H, d, 5.9 Hz), 3.99 (1H, d, 15.8 Hz), 3.83 (3H,s), 3.82 (3H, s), 3.81 (3H, s), 3.18 (1H, br), 2.96 (1H, m), 2.33 (1H,ddd, 15.2, 3.6, 3.6 Hz), 1.95 (1H, ddd, 15.2, 3.9, 3.9 Hz), 1.52 (3H, d,6.6 Hz).

EXAMPLE 22

[0202] Compound 22:

[0203] Isomer ratio: about 3:1

[0204] FAB-MS m/z: 528 [M+H]⁺

[0205] Major component: ¹H-NMR (CDCl₃) δ (ppm): 8.57 (1H, br s), 8.47(1H, br d, 4.3 Hz), 7.81 (1H, ddd, 8.2, 2.0, 1.7 Hz), 7.36 (1H, dd, 7.9,4.6 Hz), 7.20 (1H, dd, 15.8, 11.2 Hz), 6.93 (1H, t, 6.3 Hz), 6.65 (1H,d, 16.2 Hz), 6.46 (1H, s), 6.10 (1H, dd, 10.6, 9.9 Hz), 5.67 (1H, dd,10.2, 3.0 Hz), 5.45 (1H, m), 4.48-4.64 (5H, m), 3.90 (1H, d, 15.2 Hz),3.15 (1H, br), 2.94 (1H, br d, 8.9 Hz), 2.31 (1H, ddd, 15.2, 3.3, 3.3Hz), 1.92 (1H, m), 1.52 (3H, d, 6.9 Hz).

EXAMPLE 23

[0206] Compound 23:

[0207] Isomer ratio: about 3:1

[0208] FAB-MS m/z: 544 [M+H]⁺

[0209] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.70 (1H, br), 9.02(1H, br), 7.22 (1H, dd, 15.8, 11.2 Hz), 6.61-6.65 (2H, m), 6.60 (1H, s),6.53 (1H, m), 6.15 (1H, dd, 10.9, 10.6 Hz), 5.89-5.98 (2H, m), 5.68 (1H,dd, 10.2, 3.0 Hz), 5.47 (1H, m), 4.64 (1H, d, 15.5 Hz), 4.61 (1H, br),4.58 (1H, d, 16.2 Hz), 4.06 (1H, br), 3.41-3.60 (2H, m), 3.54 (3H, s),3.23 (1H, br), 3.00 (1H, m), 2.81 (2H, m), 2.34 (1H, ddd, 15.2, 3.3, 3.3Hz), 1.96 (1H, ddd, 16.2, 4.0, 4.0 Hz), 1.55 (3H, d, 6.6 Hz).

EXAMPLE 24

[0210] Compounds 24 and 25:

[0211] Compound 24:

[0212] FAB-MS m/z: 548 [M+H]⁺

[0213]¹H-NMR (CDCl₃) δ (ppm): 7.61 (1H, br), 7.16 (1H, dd, 16.0, 11.4Hz), 6.85 (2H, br), 6.60 (1H, d, 16.2 Hz), 6.45 (1H, s), 5.79 (1H, dd,11.2, 10.9 Hz), 5.57 (1H, dd, 10.2, 3.0 Hz), 5.43 (1H, m), 4.70 (1H,br), 4.67 (1H, d, 15.8 Hz), 4.59 (1H, d, 15.8 Hz), 3.95 (1H, br),3.51-3.72 (2H, m), 3.15 (1H, br), 2.93 (1H, br d, 8.6 Hz), 2.80 (2H, t,5.6 Hz), 2.72 (4H, br), 2.30 (1H, ddd, 14.9, 3.3, 3.3 Hz), 1.98 (1H,ddd, 14.9, 4.3, 4.0 Hz), 1.52 (3H, d, 6.6 Hz), 1.45-1.63 (6H, br).

[0214] Compound 25:

[0215] FAB-MS m/z: 548 [M+H]⁺

[0216]¹H-NMR (CDCl₃) δ (ppm): 8.58 (1H, br), 7.05 (1H, dd, 16.2, 11.2Hz), 6.29 (1H, s), 5.98 (1H, d, 16.2 Hz), 5.98 (1H, dd, 10.9, 9.2 Hz),5.55 (1H, br d, 10.2 Hz), 5.45 (1H, m), 4.78 (1H, d, 15.8 Hz), 4.68 (1H,d, 15.5 Hz), 4.07 (2H, br), 3.98 (1H, br), 3.69 (1H, br), 2.84-3.04 (8H,m), 2.22 (1H, br d, 14.9 Hz), 2.04 (1H, ddd, 14.5, 4.6, 4.3 Hz), 1.54(3H, d, 6.9 Hz), 1.20-1.48 (6H, br), 1.57 (3H, d, 6.9 Hz).

EXAMPLE 25

[0217] Compound 26:

[0218] Isomer ratio: about 3:1

[0219] FAB-MS m/z: 562 [M+H]⁺

[0220] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.92 (1H, br), 9.00(1H, br), 7.17 (1H, m), 7.05 (1H, m), 6.81 (1H, d, 15.8 Hz), 6.56 (1H,s), 6.16 (1H, t, 10.6 Hz), 5.63 (1H, dd, 10.4, 3.1 Hz), 5.44 (1H, m),4.64 (1H, d, 19.5 Hz), 4.60 (1H, br), 4.57 (1H, d, 17.8 Hz), 4.06 (1H,br), 3.40 (2H, t, 6.9 Hz), 3.25-3.36 (4H, m), 3.21 (1H, br), 2.96 (1H,br d, 8.2 Hz), 2.30-2.42 (3H, m), 2.03 (2H, t, 7.6 Hz), 2.00 (1H, m),1.77 (2H, m), 1.54 (3H, d, 6.6 Hz).

EXAMPLE 26

[0221] Compound 27:

[0222] Isomer ratio: about 3:1

[0223] FAB-MS m/z: 505 [M+H]⁺

[0224] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.75 (1H, br), 8.50(1H, br), 7.23 (1H, dd, 16.0, 11.4 Hz), 6.67 (1H, d, 16.2 Hz), 6.61 (1H,s), 6.32 (1H, d, 7.6 Hz), 6.14 (1H, dd, 11.9, 10.2 Hz), 5.68 (1H, dd,10.4, 3.1 Hz), 5.49 (1H, m), 4.67 (1H, d, 15.8 Hz), 4.58 (2H, s), 4.26(1H, m), 3.99 (1H, d, 15.8 Hz), 3.19 (1H, br), 2.96 (1H, m), 2.33 (1H,ddd, 15.2, 3.3, 3.3 Hz), 1.89-2.04 (3H, m), 1.58-1.66 (4H, m), 1.55 (3H,d, 6.6 Hz), 1.38-1.43 (2H, m).

EXAMPLE 27

[0225] Compound 28:

[0226] Isomer ratio: about 3:1

[0227] FAB-MS m/z: 513 [M+H]⁺

[0228] Major component: 1H-NMR (CDCl₃) δ (ppm): 10.76 (1H, br),7.48-7.56 (2H, m), 7.25-7.37 (3H, m), 7.07-7.16 (2H, m), 6.77 (1H, d,16.2 Hz), 6.61 (1H, s), 6.21 (1H, dd, 11.6, 10.6 Hz), 5.74 (1H, dd,10.2, 3.6 Hz), 5.52 (1H, m), 4.80 (1H, br), 4.73 (2H, s), 4.12 (1H, br),3.23 (1H, br), 2.99 (1H, ddd, 8.3, 3.3, 2.6 Hz), 2.36 (1H, ddd, 15.2,3.6, 3.3 Hz), 1.99 (1H, ddd, 15.2, 4.0, 4.0 Hz), 1.57 (3H, d, 6.9 Hz).

EXAMPLE 28

[0229] Compound 29:

[0230] Isomer ratio: about 4:1

[0231] FAB-MS m/z: 555 [M+H]⁺

[0232] Major component: ¹H-NMR (CDCl₃) δ (ppm): 8.00 (1H, br s), 7.43(2H, d, 8.6 Hz), 7.19 (2H, d, 8.3 Hz), 7.20 (1H, m), 6.77 (1H, d, 16.2Hz), 6.59 (1H, s), 6.19 (1H, dd, 10.6, 9.9 Hz), 5.73 (1H, dd, 10.2, 3.3Hz), 5.49 (1H, m), 4.72 (2H, s), 4.72 (1H, br), 4.09 (1H, br), 3.22 (1H,br), 2.82-3.01 (2H, m), 2.35 (1H, dd, 15.2, 3.3, 3.3 Hz), 1.98 (1H, ddd,15.2, 4.0, 4.0 Hz), 1.55 (3H, d, 6.6 Hz), 1.22 (6H, d, 6.9 Hz).

EXAMPLE 29

[0233] Compound 30:

[0234] Isomer ratio: about 3:1

[0235] FAB-MS m/z: 543 [M+H]⁺

[0236] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.97 (1H, d, 9.2 Hz),7.38-7.44 (2H, m), 7.26 (1H, dd, 15.8, 11.5 Hz), 6.81-6.86 (2H, m), 6.75(1H, d, 16.2 Hz), 6.56 (1H, s), 6.16 (1H, dd, 11.6, 10.2 Hz), 5.69 (1H,dd, 10.6, 3.3 Hz), 5.47 (1H, m), 4.73 (1H, d, 16.5 Hz), 4.67 (1H, d,14.9 Hz), 4.64 (1H, br), 4.04 (1H, d, 14.5 Hz), 3.75 (3H, s), 3.20 (1H,br), 2.96 (1H, ddd, 9.9, 3.6, 2.3 Hz), 2.33 (1H, ddd, 15.2, 3.6, 3.3Hz), 1.94 (1H, ddd, 15.2, 4.0, 4.0 Hz), 1.53 (3H, d, 6.9 Hz).

EXAMPLE 30

[0237] Compound 31:

[0238] Isomer ratio: about 3:1

[0239] FAB-MS m/z: 584 [M+H]⁺

[0240] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.98 (1H, br s), 7.32(2H, d, 8.9 Hz), 7.29 (1H, m), 6.75 (1H, d, 16.2 Hz), 6.64 (2H, d, 8.9Hz), 6.58 (1H, s), 6.18 (1H, dd, 11.9, 9.9 Hz), 5.71 (1H, dd, 10.2, 3.0Hz), 5.48 (1H, m), 4.72 (1H, d, 16.8 Hz), 4.71 (2H, s), 4.04 (1H, d,15.8 Hz), 3.31 (4H, q, 7.1 Hz), 3.21 (1H, br), 2.99 (1H, ddd, 8.6, 2.6,2.3 Hz), 2.34 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.96 (1H, ddd, 15.2, 4.0,4.0 Hz), 1.55 (3H, d, 6.6 Hz), 1.12 (6H, t, 7.1 Hz).

EXAMPLE 31

[0241] Compound 32:

[0242] Isomer ratio: about 3:1

[0243] FAB-MS m/z: 514 [M+H]⁺

[0244] Major component: ¹H-NMR (CDCl₃) δ (ppm): 8.56 (1H, br d, 7.9 Hz),8.46 (1H, m), 8.30-8.34 (2H, m), 7.31-7.42 (2H, m), 6.76 (1H, d, 16.2Hz), 6.52 (1H, s), 6.17 (1H, dd, 10.9, 9.9 Hz), 5.72 (1H, dd, 10.2, 3.0Hz), 5.48 (1H, m), 4.80 (1H, br), 4.77 (1H, d, 16.5 Hz), 4.70 (1H, d,16.5 Hz), 4.03 (1H, d, 16.5 Hz), 3.20 (1H, br), 2.95 (1H, m), 2.34 (1H,ddd, 15.2, 3.3, 3.3 Hz), 1.97 (1H, ddd, 15.2, 4.3, 4.0 Hz), 1.56 (3H, d,6.9 Hz).

EXAMPLE 32

[0245] Compound 33:

[0246] Isomer ratio: about 3:1

[0247] FAB-MS m/z: 480 [M+H]⁺

[0248] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.77 (1H, br s), 7.24(1H, dd, 16.2, 11.2 Hz), 7.00 (1H, br s), 6.67 (1H, d, 16.5 Hz), 6.64(1H, s), 6.17 (1H, dd, 11.2, 10.6 Hz), 5.71 (1H, dd, 10.2, 3.0 Hz), 5.53(1H, m), 4.75 (1H, br), 4.62 (2H, s), 4.08 (1H, br), 3.22 (1H, br), 2.99(1H, br d, 8.3 Hz), 2.63 (6H, s), 2.36 (1H, ddd, 14.8, 3.6, 3.6 Hz),1.99 (1H, ddd, 15.5, 8.6, 4.1 Hz), 1.57 (3H, d, 6.6 Hz).

EXAMPLE 33

[0249] Compound 34:

[0250] Isomer ratio: about 3:1

[0251] FAB-MS m/z: 496 [M+H]⁺

[0252] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.70 (1H, br), 7.72(1H, br), 7.24 (1H, dd, 15.2, 11.5 Hz), 6.66 (1H, d, 16.2 Hz), 6.60 (1H,s), 6.17 (1H, dd, 11.9, 10.2 Hz), 5.72 (1H, dd, 10.4, 3.5 Hz), 5.51 (1H,m), 4.70 (1H, br), 4.70 (2H, s), 4.10 (1H, br), 3.62 (2H, t, 4.6 Hz),2.96-2.98 (3H, m), 2.36 (1H, ddd, 15.5, 3.8, 3.3 Hz), 2.00 (1H, ddd,15.5, 8.6, 4.0 Hz), 1.58 (3H, d, 6.9 Hz).

EXAMPLE 34

[0253] Compound 35:

[0254] Isomer ratio: about 3:1

[0255] FAB-MS m/z: 528 [M+H]⁺

[0256] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.75 (1H, br), 8.01(1H, br s), 7.19-7.25 (2H, m), 7.00 (1H, dd, 15.2, 10.9 Hz), 6.86-6.93(4H, m), 6.71 (1H, d, 16.2 Hz), 6.58 (1H, s), 6.18 (1H, dd, 10.6, 9.9Hz), 5.72 (1H, dd, 10.4, 3.1 Hz), 5.50 (1H, m), 4.82 (1H, br), 4.76 (2H,s), 4.12 (1H, d, 14.2 Hz), 3.22 (1H, br), 2.97 (1H, m), 2.35 (1H, ddd,15.2, 3.6, 3.3 Hz), 1.99 (1H, ddd, 15.2, 8.6, 4.3 Hz), 1.55 (3H, d, 6.6Hz).

EXAMPLE 35

[0257] Compound 36:

[0258] Isomer ratio: about 4:1

[0259] FAB-MS m/z: 529 [M+H]⁺

[0260] Major component: ¹H-NMR (CDCl₃) δ (ppm): 8.30 (1H, br), 8.10 (1H,br d, 4.6 Hz), 8.07 (1H, br), 7.52 (1H, dd, 7.6, 6.6 Hz), 7.22 (1H, m),6.67-6.87 (3H, m), 6.54 (1H, s), 6.15 (1H, dd, 11.2, 10.9 Hz), 5.70 (1H,dd, 10.2, 3.0 Hz), 5.48 (1H, m), 4.74 (2H, s), 4.67 (1H, d, 15.5 Hz),4.08 (1H, br), 3.23 (1H, br), 2.98 (1H, br d, 8.3 Hz), 2.35 (1H, br d,15.5 Hz), 1.98 (1H, m), 1.55 (3H, d, 6.6 Hz).

EXAMPLE 36

[0261] Compound 37:

[0262] Isomer ratio: about 2:1

[0263] FAB-MS m/z: 520 [M+H]⁺

[0264] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.80 (1H, br), 8.50(1H, br), 7.25 (1H, dd, 15.8, 11.2 Hz), 7.06 (1H, s), 6.67 (1H, d, 13.5Hz), 6.64 (1H, s), 6.16 (1H, dd, 11.2, 10.9 Hz), 5.70 (1H, dd, 10.2, 3.0Hz), 5.50 (1H, m), 4.69 (1H, d, 15.8 Hz), 4.62 (2H, s), 4.01 (1H, d,14.9 Hz), 3.19 (1H, br), 2.96 (1H, m), 2.73 (4H, br), 2.34 (1H, ddd,15.2, 3.6, 3.0 Hz), 1.96 (1H, ddd, 15.2, 8.4, 4.1 Hz), 1.66 (6H, br),1.56 (3H, d, 6.9 Hz).

EXAMPLE 37

[0265] Compound 38:

[0266] Isomer ratio: about 2:1

[0267] FAB-MS m/z: 535 [M+H]⁺

[0268] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.25 (1H, m), 7.14 (1H,s), 6.68 (1H, 16.2 Hz), 6.44 (1H, s), 6.16 (1H, dd, 11.2, 10.9 Hz), 5.72(1H, dd, 10.1, 2.8 Hz), 5.49 (1H, m), 4.74 (1H, br), 4.64 (1H, 16.5 Hz),4.57 (1H, 16.5 Hz), 4.01 (1H, br), 3.20 (1H, br), 2.93-2.99 (5H, br),2.76 (4H, br), 2.45 (1H, m), 2.37 (6H, s), 1.97 (1H, m), 1.56 (3H, d,6.6 Hz).

EXAMPLE 38

[0269] Compound 39:

[0270] According to (1-1) described in Example 1, an oxime derivativewas prepared from radicicol and trifluoroacetate of compound a, and thencompound 39 was prepared according to (1-2) described in Example 1.

[0271] Isomer ratio: about 5:1

[0272] FAB-MS m/z: 589 [M+H]⁺

[0273] Major component: ¹H-NMR (CDCl₃+CD₃OD) δ (ppm): 10.85 (1H, br),7.90 (1H, br), 7.16 (1H, m), 6.67 (1H, d, 15.8 Hz), 6.58 (1H, s), 6.15(1H, dd, 11.6, 10.6 Hz), 5.64 (1H, br d, 9.9 Hz), 5.50 (1H, m), 4.75(1H, br), 4.19 (2H, m), 4.02 (1H, br), 3.55 (2H, br), 3.40 (2H, br),3.19 (1H, br), 2.97 (1H, ddd, 7.9, 2.4, 2.4 Hz), 2.29-2.36 (3H, m), 1.99(1H, ddd, 15.2, 8.9, 4.0 Hz), 1.59-1.64 (10H, br), 1.56 (3H, d, 6.6 Hz),1.37 (6H, br).

EXAMPLE 39

[0274] Compound 40:

[0275] According to Example 38, compound 40 was prepared from atrifluoroacetate of compound b.

[0276] Isomer ratio: about 2:1

[0277] FAB-MS m/z: 631 [M+H]⁺

[0278] Major component: ¹H-NMR (CDCl₃) δ (ppm): 11.03 (1H, br), 8.72(1H, br), 7.16 (1H, dd, 15.8, 12.9 Hz), 6.67 (1H, d, 16.2 Hz), 6.58 (1H,s), 6.14 (1H, dd, 11.2, 9.9 Hz), 5.62 (1H, br d, 9.6 Hz), 5.49 (1H, m),4.72 (1H, br), 4.05-4.21 (3H, m), 3.56 (2H, br), 3.40 (2H, br), 3.21(1H, br), 2.97 (1H, ddd, 8.3, 2.3, 2.3 Hz), 2.29-2.37 (3H, m), 2.01 (1H,ddd, 15.2, 8.6, 4.3 Hz), 1.60-1.76 (10H, br), 1.55 (3H, d, 6.6 Hz), 1.28(12H, br).

EXAMPLE 40

[0279] Compound 41

[0280] According to (1-2) described in Example 1, 14 mg (yield, 10%) ofcompound 41 was prepared from 100 mg (0.228 mmol) of compound (K), 52 mg(0.342 mmol) of HOBt, 65 mg (0.342 mmol) of EDCI and 69 mg (0.274 mmol)of pentaethylene glycol monomethyl ether. The thus prepared compound 41was found to be a mixture of oxime-based isomers (about 3:1) accordingto ¹H-NMR.

[0281] FAB-MS m/z: 672 [M+H]⁺

[0282] Major component: ¹H-NMR (CDCl₃) δ (ppm) : 7.20 (1H, m), 6.77 (1H,d, 16.2 Hz), 6.58 (1H, s), 6.16 (1H, dd, 11.6, 10.6 Hz), 5.66 (1H, br d,9.6 Hz), 5.53 (1H, m), 4.77 (1H, br), 4.76 (1H, d, 16.5 Hz), 4.69 (1H,16.2 Hz), 4.33 (2H, m), 4.00 (1H, br), 3.72 (2H, m), 3.64-3.65 (14H, m),3.53-3.56 (2H, m), 3.37 (3H, s), 3.20 (1H, br), 2.98 (1H, br d, 8.6 Hz),2.34 (1H, ddd, 15.2, 3.6, 3.3 Hz), 2.00 (1H, ddd, 15.5, 4.3, 4.0 Hz),1.56 (3H, d, 6.6 Hz).

EXAMPLE 41

[0283] Compound 42:

[0284] According to Example 40, compound 42 was prepared from compound(K).

[0285] Isomer ratio: about 3:1

[0286] FAB-MS m/z: 584 [M+H]⁺

[0287] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.80 (1H, br), 7.20(1H, m), 6.77 (1H, d, 16.2 Hz), 6.58 (1H, br), 6.58 (1H, s), 6.16 (1H,t, 10.9 Hz), 5.67 (1H, br d, 9.9 Hz), 5.51 (1H, m), 4.78 (1H, br), 4.76(1H, d, 16.5 Hz), 4.69 (1H, d, 16.5 Hz), 4.31-4.35 (2H, m), 4.02 (1H,br), 3.73 (2H, t, 4.8 Hz), 3.63-3.67 (6H, m), 3.54-3.57 (2H, m), 3.38(3H, s), 3.19 (1H, br), 2.98 (1H, ddd, 9.2, 3.3, 3.3 Hz), 2.34 (1H, ddd,15.2, 3.6, 3.3 Hz), 1.98 (1H, ddd, 18.8, 4.0, 4.0 Hz), 1.57 (3H, d, 6.9Hz).

EXAMPLE 42

[0288] Compound 43:

[0289] According to (1-1) described in Example 1, 338 mg (yield, 53%) ofcompound 43 was prepared from 500 mg (1.37 mmol) of radicicol and 438 mg(2.74 mmol) of o-benzylhydroxylamine hydrochloride. The thus preparedcompound 43 was found to be a mixture of oxime-based isomers (about 2:1)according to ¹H-NMR.

[0290] FAB-MS m/z: 470 [M+H]⁺

[0291] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.10-7.50 (6H, m), 6.78(1H, d, 15.8 Hz), 6.42 (1H, s), 6.18 (1H, t, 10.9 Hz), 5.59 (1H, dd,10.9, 3.3 Hz), 5.30 (1H, m), 5.16 (2H, s), 3.91 (1H, d, 16.3 Hz), 3.81(1H, d, 16.3 Hz), 3.32 (1H, m), 3.01 (1H, dt, 7.9, 3.3 Hz), 2.41 (1H,dd, 14.3, 3.5 Hz), 1.55 (1H, m), 1.52 (3H, d, 6.4 Hz).

EXAMPLE 43

[0292] Compound 44:

[0293] A 205 mg (1.12 mmol) portion of compound c was dissolved in 3 mlof methanol, and the solution was mixed with 0.467 ml of 12 Nhydrochloric acid and stirred at room temperature for 2.5 hours. Thesolvent was evaporated under reduced pressure, the thus prepared residuewas dissolved in 2 ml of pyridine and mixed with 136 mg (0.37 mmol) ofradicicol which had been dissolved in 2 ml of pyridine, and then themixture was stirred at room temperature for 138 hours. The reactionsolution was mixed with 0.5 N hydrochloric acid and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine anddried with anhydrous sodium sulfate, and then the solvent was evaporatedunder reduced pressure. The resulting residue was purified by thin layerchromatography (chloroform/methanol=5/1, then chloroform/acetone=4/1) toobtain 119 mg (yield, 65%) of compound 44. The thus prepared compound 44was found to be a mixture of oxime-based isomers (about 2.5:1) accordingto ¹H-NMR.

[0294] FAB-MS m/z: 486 [M+H]⁺

[0295] Major component: ¹H-NMR (CDCl₃) δ (ppm): 11.00 (1H, br), 9.09(1H, br), 7.22-7.32 (3H, m), 7.00 (1H, d, 8.2 Hz), 6.91 (1H, ddd, 7.6,7.3, 1.1 Hz), 6.64 (1H, d, 15.8 Hz), 6.57 (1H, s), 6.14 (1H, dd, 9.9,9.6 Hz), 5.69 (1H, br d, 10.2 Hz), 5.47 (1H, m), 5.15 (1H, d, 13.5 Hz),5.08 (1H, d, 12.9 Hz), 4.80 (1H, br), 3.99 (1H, br), 3.20 (1H, br), 2.96(1H, ddd, 8.3, 2.6, 2.5 Hz), 2.31 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.97(1H, ddd, 14.9, 8.6, 4.0 Hz), 1.55 (3H, d, 6.6 Hz).

EXAMPLES 44-49

[0296] According to Example 43, compounds 45 to 50 were prepared fromradicicol and compounds d to i, respectively.

EXAMPLE 44

[0297] Compound 45:

[0298] Isomer ratio: about 1.7:1

[0299] FAB-MS m/z: 502 [M+H]⁺

[0300] Major component: ¹H-NMR (CDCl₃+CD₃OD) δ (ppm): 7.11 (1H, dd,16.2, 11.2 Hz), 6.67 (1H, d, 16.2 Hz), 6.37 (1H, s), 6.35 (1H, d, 2.0Hz), 6.32 (1H, d, 2.0 Hz), 6.18 (1H, d, 2.0 Hz), 6.05 (1H, t, 10.6 Hz),5.54 (1H, dd, 10.1, 2.8 Hz), 5.36 (1H, m), 4.97 (2H, s), 4.36 (1H, d,16.2 Hz), 3.86 (1H, d, 18.1 Hz), 3.16 (1H, br), 2.91 (1H, br d, 8.9 Hz),2.26 (1H, ddd, 14.9, 3.3, 3.0 Hz), 1.77 (1H, ddd, 14.9, 4.3, 4.0 Hz),1.47 (3H, d, 6.6 Hz).

EXAMPLE 45

[0301] Compound 46:

[0302] Isomer ratio: about 1.8:1

[0303] FAB-MS m/z: 560 [M+H]⁺

[0304] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.17 (1H, dd, 15.8, 11.5Hz), 6.73 (1H, d, 16.2 Hz), 6.63 (2H, s), 6.54 (1H, s), 6.13 (1H, dd,12.5, 10.6 Hz), 5.60 (1H, br d, 11.2 Hz), 5.49 (1H, m), 5.11 (2H, s),4.69 (1H, br), 4.04 (1H, br), 3.85 (3H, s), 3.84 (6H, s), 3.18 (1H, br),2.96 (1H, br d, 8.9 Hz), 2.32 (1H, ddd, 14.9, 3.6, 3.3 Hz), 1.95 (1H,ddd, 14.5, 9.4, 4.1 Hz), 1.54 (3H, d, 6.6 Hz).

EXAMPLE 46

[0305] Compound 47:

[0306] Isomer ratio: about 1.8:1

[0307] FAB-MS m/z: 500 [M+H]⁺

[0308] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.16 (1H, dd, 16.5, 11.2Hz), 6.74 (1H, d, 16.2 Hz), 6.52 (1H, s), 6.21 (1H, d, 2.0 Hz), 6.18(1H, d, 2.0 Hz), 6.14 (1H, dd, 10.9, 10.6 Hz), 5.98 (1H, dd, 3.6, 2.0Hz), 5.65 (1H, br d, 10.2 Hz), 5.49 (1H, m), 5.02 (1H, s), 4.70 (1H,br), 3.99 (1H, br), 3.18 (1H, br), 2.96 (1H, ddd, 8.9, 3.3, 2.6 Hz),2.32 (1H, ddd, 15.2, 3.6, 3.3 Hz), 1.96 (1H, ddd, 15.0, 9.4, 4.5 Hz),1.55 (3H, d, 6.9 Hz).

EXAMPLE 47

[0309] Compound 48:

[0310] Isomer ratio: about 3:1

[0311] FAB-MS m/z: 527 [M+H]⁺

[0312] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.15 (1H, m), 7.14 (2H,d, 8.6 Hz), 6.72 (2H, d, 8.6 Hz), 6.69 (1H, d, 15.8 Hz), 6.56 (1H, s),6.14 (1H, dd, 11.2, 10.6 Hz), 5.64 (1H, dd, 10.2, 3.3 Hz), 5.50 (1H, m),4.73 (1H, br), 4.25-4.38 (2H, m), 4.06 (1H, br), 3.21 (1H, br),2.95-3.00 (3H, m), 2.92 (6H, s), 2.34 (1H, ddd, 15.2, 3.5, 3.3 Hz), 1.99(1H, ddd, 14.8, 8.9, 4.0 Hz), 1.57 (3H, d, 6.9 Hz).

EXAMPLE 48

[0313] Compound 49:

[0314] Isomer ratio: about 2.4:1

[0315] FAB-MS m/z: 582 [M+H]⁺

[0316] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.38 (2H, d, 7.9 Hz),7.14-7.32 (1H, m), 7.23 (2H, d, 7.6 Hz), 6.71 (1H, d, 15.8 Hz), 6.38(1H, s), 6.15 (1H, dd, 11.9, 10.6 Hz), 5.64 (1H, dd, 10.2, 2.0 Hz), 5.47(1H, m), 5.17 (2H, s), 4.70 (1H, br), 3.68 (1H, br), 3.66 (2H, s), 3.21(1H, br), 2.97 (1H, br d, 8.3 Hz), 2.61 (8H, br), 2.37 (3H, s), 2.33(1H, ddd, 14.2, 3.6, 3.3 Hz), 1.99 (1H, m), 1.54 (3H, d, 6.6 Hz).

EXAMPLE 49

[0317] Compound 50:

[0318] Isomer ratio: about 1.4:1

[0319] FAB-MS m/z: 577 [M+H]⁺

[0320] Major component: ¹H-NMR (CDCl₃) δ (ppm): 7.88 (1H, d, 7.9 Hz),7.71 (1H, m), 7.57 (1H, dd, 7.9, 7.3 Hz), 7.42 (1H, d, 8.3, 7.3 Hz),7.19 (1H, m), 6.79 (1H, d, 16.2 Hz), 6.56 (1H, s), 6.17 (1H, dd, 10.9,9.6 Hz), 5.59-5.72 (3H, m), 5.51 (1H, m), 4.66 (1H, br), 3.96 (1H, br),3.20 (1H, br), 2.99 (1H, ddd, 8.6, 2.6, 2.6 Hz), 2.80 (6H, s), 2.34 (1H,ddd, 15.2, 3.6, 3.3 Hz), 1.97 (1H, m), 1.56 (3H, d, 6.6 Hz).

EXAMPLE 50

[0321] Compound 51:

[0322] A 565 mg (4.55 mmol) portion of compound j was dissolved in 10 mlof pyridine, and the solution was mixed with 0.4 ml of concentratedhydrochloric acid and 664 mg (1.82 mmol) of radicicol and stirred atroom temperature for 21 hours. The reaction solution was mixed with asaturated ammonium chloride aqueous solution and extracted with ethylacetate, the ethyl acetate layer was washed with saturated brine anddried with anhydrous sodium sulfate, and then the solvent was evaporatedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (chloroform/methanol=40/1) to obtain 694 mg(yield, 81%) of compound 51.

[0323] Isomer ratio: about 2:1

[0324] FAB-MS m/z: 471 [M+H]⁺

[0325] Major component: ¹H-NMR (CD₃OD) δ (ppm): 8.48 (1H, d, 4.0 Hz),7.84 (1H, dt, 7.6, 1.8 Hz), 7.53 (1H, m), 7.33 (1H, m), 7.26 (1H, dd,16.2, 11.2 Hz), 6.87 (1H, d, 15.8 Hz), 6.40 (1H, s), 6.17 (1H, t, 10.9Hz), 5.60 (1H, dd, 10.9, 3.0 Hz), 5.28 (1H, m), 5.23 (2H, s), 3.92 (1H,d, 16.2 Hz), 3.77 (1H, d, 16.2 Hz), 3.33 (1H, m), 3.01 (1H, m), 2.40(1H, ddd, 14.2, 3.6, 3.3 Hz), 1.58 (1H, ddd, 13.8, 8.9, 4.4 Hz), 1.51(3H, d, 6.3 Hz).

EXAMPLE 51

[0326] Compounds 52 and 53:

[0327] A mixture of compounds 52 and 53 (about 4:1) was prepared fromradicicol and compound k according to Example 50, 380 mg of the thusprepared mixture of compounds 52 and 53 (about 4:1) was separated byhigh performance liquid chromatography (column: YMC-Pack ODS AM,SH-365-10AM, 500×30 mm I.D., eluent: 50 mM4 phosphate buffer (pH7.3)/methanol=47/53, flow rate: 40 ml/min, detection: UV 276 nm), theeluate was extracted with ethyl acetate, washed with saturated brine anddried with anhydrous sodium sulfate, and then the solvent was evaporatedunder reduced pressure. Each of the resulting residues was powdered froma mixed solvent of ethanol and water to obtain 219 mg of compound 52 and133 mg of compound 53.

[0328] Compound 52:

[0329] FAB-MS m/z: 471 [M+H]⁺

[0330]¹H-NMR (CD₃OD) δ (ppm): 8.58 (1H, d, 2.0 Hz), 8.47 (1H, dd, 5.0,2.0 Hz), 7.89 (1H, dd, 7.9, 2.0 Hz), 7.43 (1H, ddd, 7.9, 5.0, 2.0 Hz),7.26 (1H, dd, 15.8, 10.9 Hz), 6.76 (1H, d, 15.8 Hz), 6.41 (1H, s), 6.16(1H, t, 10.9 Hz), 5.61 (1H, dd, 10.9, 3.0 Hz), 5.31 (1H, m), 5.22 (2H,s), 3.91 (1H, d, 15.8 Hz), 3.81 (1H, d, 16.3 Hz), 3.35 (1H, m), 3.02(1H, m), 2.42 (1H, dt, 15.3, 4.0 Hz), 1.58 (1H, ddd, 13.8, 8.9, 4.4 Hz),1.52 (3H, d, 6.4 Hz).

[0331] Compound 53:

[0332] FAB-MS m/z: 471 [M+H]⁺

[0333]¹H-NMR (CD₃OD) δ (ppm): 8.61 (1H, d, 2.0 Hz), 8.49 (1H, dd, 5.0,2.0 Hz), 7.93 (1H, dd, 7.9, 2.0 Hz), 7.45 (1H, ddd, 7.9, 5.0, 2.0 Hz),7.15 (1H, dd, 16.2, 10.9 Hz), 6.41 (1H, s), 6.12 (1H, d, 15.8 Hz), 6.09(1H, t, 10.9 Hz), 5.48 (1H, dd, 10.9, 3.0 Hz), 5.31 (1H, m), 5.26 (2H,s), 4.64 (1H, d, 16.4 Hz), 3.40 (1H, d, 16.2 Hz), 3.35 (1H, m), 2.96(1H, dt, 8.9, 2.6 Hz), 2.42 (1H, dt, 14.5, 3.0 Hz), 1.60 (1H, m), 1.50(3H, d, 6.4 Hz).

EXAMPLE 52

[0334] Compound 54:

[0335] According to Example 50, compound 54 was prepared from radicicoland compound m.

[0336] Isomer ratio: about 2:1

[0337] FAB-MS m/z: 471 [M+H]⁺

[0338] Major component: ¹H-NMR (CD₃OD) δ (ppm): 8.60 (2H, m), 7.50 (1H,m), 7.29 (1H, dd, 16.2, 11.2 Hz), 6.85 (1H, d, 11.2 Hz), 6.43 (1H, s),6.18 (1H, t, 10.9 Hz), 5.62 (1H, dd, 10.6, 3.3 Hz), 5.30 (1H, m), 5.23(2H, s), 3.91 (1H, d, 16.2 Hz), 3.81 (1H, d, 16.2 Hz), 3.35 (1H, m),3.02 (1H, dt, 7.9, 3.3 Hz), 2.42 (1H, dd, 14.5, 4.0 Hz), 1.59 (1H, ddd,13.8, 8.9, 4.4 Hz), 1.52 (3H, d, 6.3 Hz).

EXAMPLE 53

[0339] Compound 55:

[0340] According to Example 43, compound 55 was prepared from radicicoland compound n.

[0341] Isomer ratio: about 1.5:1

[0342] FAB-MS m/z: 499 [M+H]⁺

[0343] Major component: ¹H-NMR (CDCl₃) δ (ppm): 8.47 (1H, s), 8.42 (1H,d, 5.0 Hz), 7.62 (1H, d, 7.9 Hz), 7.28 (1H, dd, 7.6, 4.9 Hz), 7.17 (1H,dd, 15.5, 11.5 Hz), 6.63 (1H, d, 16.2 Hz), 6.52 (1H, s), 6.15 (1H, dd,11.6, 11.2 Hz), 5.65 (1H, br d, 9.9 Hz), 5.50 (1H, m), 4.71 (1H, d, 15.5Hz), 4.20 (2H, t, 6.8 Hz), 4.01 (1H, br), 3.19 (1H, br), 2.97 (1H, br d,8.6 Hz), 2.77 (2H, t, 7.3 Hz), 2.33 (2H, ddd, 15.2, 3.3, 3.0 Hz), 2.07(2H, m), 1.94 (1H, ddd, 16.8, 8.3, 4.0 Hz), 1.56 (3H, d, 6.9 Hz).

EXAMPLE 54

[0344] Compound 56:

[0345] According to Example 43, compound 56 was prepared from radicicoland compound o.

[0346] Isomer ratio: about 3:1

[0347] FAB-MS m/z: 487 [M+H]⁺

[0348] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.95 (1H, br), 9.36(1H, br), 8.15 (1H, d, 4.3 Hz), 7.34 (1H, d, 8.3 Hz), 7.20-7.30 (2H, m),6.69 (1H, d, 16.2 Hz), 6.57 (1H, s), 6.15 (1H, dd, 10.9, 10.6 Hz), 5.70(1H, br d, 11.2 Hz), 5.48 (1H, m), 5.32 (1H, d, 12.5 Hz), 5.24 (1H, d,12.5 Hz), 4.77 (1H, br), 4.03 (1H, br), 3.19 (1H, br), 2.96 (1H, br d,8.2 Hz), 2.32 (1H, ddd, 15.2, 3.3, 3.0 Hz), 1.97 (1H, ddd, 14.7, 8.7,4.3 Hz), 1.55 (3H, d, 6.6 Hz).

EXAMPLE 55

[0349] Compound 57:

[0350] (55-1):

[0351] A 5.00 g (13.7 mmol) portion of radicicol was dissolved in 10 mlof DMF to which, while cooling in an ice bath, were subsequently added2.80 g (41.1 mmol) of imidazole and 4.54 g (30.1 mmol) oftert-butyl(chloro)dimethylsilane, and the resulting mixture was stirredat room temperature for 3 hours. The reaction solution was mixed with asaturated ammonium chloride aqueous solution and extracted with ethylacetate, the ethyl acetate layer was washed with saturated brine anddried with anhydrous sodium sulfate, and then the solvent was evaporatedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (chloroform/methanol=100/1) to obtain 6.96 g(yield, 86%) of a di-tert-butyldimethylsilyl derivative of radicicol.

[0352] FAB-MS m/z: 593 [M+H]⁺

[0353] (55-2):

[0354] According to (1-1) described in Example 1, 18 mg (yield, 5.5%) ofcompound (L) was prepared from 319 mg (0.54 mmol) ofdi-tert-butyldimethylsilyl derivative of radicicol and 240 mg (3.45mmol) of hydroxylamine hydrochloride. The thus prepared compound (L) wasfound to be a mixture of oxime-based isomers (about 1:1) according to¹H-NMR.

[0355] FAB-MS m/z: 608 [M+N]⁺

[0356] (55-3):

[0357] A 120 mg (0.20 mmol) portion of compound (L) was dissolved in 1.7ml of THF, the resulting solution was mixed with 167 mg (0.99 mmol) of2-hydroxymethyl-3-methoxymethoxypyridine dissolved in 0.5 ml of THF,which had been prepared by dimethoxymethylation of3-hydroxy-2-pyridinecarboxylic acid and subsequent reduction withlithium aluminum hydride, 103 mg (0.39 mmol) of triphenylphosphine and0.06 ml (0.39 mmol) of DEAD, and the mixture was stirred at roomtemperature for 23 hours. The reaction solution was mixed with aphosphate buffer (pH 7) and extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine and dried with anhydroussodium sulfate, and then the solvent was evaporated under reducedpressure. The resulting residue was purified by thin layerchromatography (chloroform/methanol=100/1) to obtain 39 mg (yield, 26%)of a di-tert-butyldimethylsilyl derivative of compound 57.

[0358] FAB-MS m/z: 761 [M+H]⁺

[0359] (55-4):

[0360] A 39 mg (0.05 mmol) portion of the di-tert-butyldimethylsilylderivative of compound 57 was dissolved in 1.8 ml of THF, 0.13 ml (0.13mmol) of a 1 M TBAF/THF solution was added to the thus prepared solutionwhich was cooled at −10° C., and the resulting mixture was stirred for50 minutes at the same temperature. The reaction solution was mixed witha phosphate buffer (pH 7) and extracted with chloroform. The chloroformlayer was washed with saturated brine and dried with anhydrous sodiumsulfate, and then the solvent was evaporated under reduced pressure. Theresulting residue was purified by thin layer chromatography(chloroform/methanol=12/1) to obtain 26 mg (yield, 95%) of compound 57.The thus prepared compound 57 was found to be a mixture of oxime-basedisomers (about 1:1.7) according to ¹H-NMR.

[0361] FAB-MS m/z: 531 [M+H]⁺

[0362] Major component: ¹H-NMR (CDCl₃) δ (ppm): 11.15 (1H, br), 8.28(1H, dd, 4.6, 1.3 Hz), 7.49 (1H, d, 8.3 Hz), 7.25 (1H, dd, 8.3, 5.0 Hz),7.02 (1H, dd, 16.2, 10.9 Hz), 6.72 (1H, s), 6.13 (1H, d, 15.8 Hz), 6.09(1H, dd, 10.2, 9.6 Hz), 5.55 (1H, dd, 10.6, 2.3 Hz), 5.49 (1H, m), 5.30(2H, s), 5.23 (2H, s), 4.58 (1H, d, 16.5 Hz), 4.21 (1H, d, 16.5 Hz),3.45 (3H, s), 3.08 (1H, br), 2.90 (1H, br d, 9.9 Hz), 2.31 (1H, ddd,15.2, 3.0, 2.6 Hz), 1.90 (1H, ddd, 15.2, 10.2, 4.3 Hz), 1.53 (3H, d, 6.9Hz).

EXAMPLE 56

[0363] Compound 58:

[0364] According to Example 43, compound 58 was prepared from radicicoland compound p.

[0365] Isomer ratio: about 1.4:1

[0366] FAB-MS m/z: 487 [M+H]⁺

[0367] Major component: ¹H-NMR (CDCl₃+CD₃OD) δ (ppm): 8.15 (0.25H, dd,5.9, 3.3 Hz), 7.76 (0.25H, dd, 5.9, 3.3 Hz), 7.64 (1H, m), 7.33 (1H, dd,3.3, 2.6 Hz), 7.11 (1H, dd, 16.0, 11.4 Hz), 6.56 (1H, d, 16.2 Hz), 6.50(0.5H, d, 1.7 Hz), 6.38 (1H, s), 6.05 (1H, dd, 10.9, 9.6 Hz), 5.56 (1H,dd, 10.2, 3.0 Hz), 5.37 (1H, m), 4.86 (2H, s), 4.46 (1H, d, 16.5 Hz),3.88 (1H, d, 16.5 Hz), 3.18 (1H, br), 2.90 (1H, ddd, 8.6, 2.6, 2.3 Hz),2.27 (1H, ddd, 14.9, 4.3, 3.6 Hz), 1.79 (1H, ddd, 14.5, 8.9, 4.0 Hz),1.47 (3H, d, 6.3 Hz).

EXAMPLE 57

[0368] Compound 59:

[0369] According to (1-1) described in Example 1, compound 59 wasprepared from radicicol and a trifluoroacetate of compound q.

[0370] Isomer ratio: about 2:1

[0371] FAB-MS m/z: 504 [M+H]⁺

[0372] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.29 (1H, dd, 15.8, 11.2Hz), 6.82 (1H, d, 16.2 Hz), 6.43 (1H, s), 6.18 (1H, dd,

9 Hz), 5.67 (1H, s), 5.66 (1H, dd, 10.6, 3.6 Hz), 5.31

4.87 (2H, s), 3.95 (1H, d, 16.2 Hz), 3.84 (1H, d,

3.30 (1H, m), 3.02 (1H, dd, 5.6, 2.3 Hz), 2.43 (1H,

3.5 Hz), 1.62 (1H, m), 1.52 (3H, d, 6.6 Hz).

EXAMPLE 58

60: according to Example 43, compound 60 was prepared

cicol and compound r. ratio: about 2:1

z: 491 [M+H]⁺component: ¹H-NMR (CDCl₃) δ (ppm): 8.88 (2H, br), 7.19

6.66 (1H, d, 12.9 Hz), 6.38 (1H, s), 6.16 (1H, dd,

Hz), 5.62 (1H, br d, 10.2 Hz), 5.42 (1H, m), 4.59 (1H,

-4.00 (3H, m), 3.11-3.31 (3H, m), 2.95 (1H, br d,

.53 (3H, s), 2.11-2.33 (3H, m), 1.95 (1H, m), 1.78

1.53 (3H, d, 6.6 Hz). EXAMPLE 59

61: according to (1-1) described in Example 1, compound prepared fromradicicol and a hydrochloride of

s. ratio: about 1.8:1 z: 477 [M+H]⁺

[0373] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.27 (1H, dd, 16.5, 11.6Hz), 6.75 (1H, d, 16.5 Hz), 6.39 (1H, s), 6.15 (1H, dd, 11.6, 10.6 Hz),5.61 (1H, dd, 10.6, 3.6 Hz), 5.32 (1H, m), 4.38 (2H, m), 3.95 (2H, m),3.28 (1H, m), 3.20 (2H, m), 3.03 (4H, m), 2.95 (1H, m), 2.41 (1H, m),1.95 (4H, m), 1.66 (1H, m), 1.52 (3H, d, 6.3 Hz).

EXAMPLE 60

[0374] Compound 62:

[0375] According to (1-1) described in Example 1, compound 62 wasprepared from radicicol and a hydrochloride of compound t.

[0376] Isomer ratio: about 5:1

[0377] FAB-MS m/z: 505 [M+H]⁺

[0378] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.26 (1H, dd, 15.8, 10.9Hz), 6.72 (1H, d, 16.2 Hz), 6.42 (1H, s), 6.16 (1H, dd, 11.9, 10.6 Hz),5.62 (1H, dd, 10.6, 3.6 Hz), 5.30 (1H, m), 4.23 (2H, dd, 12.5, 6.3 Hz),3.96 (1H, d, 16.2 Hz), 3.81 (1H, d, 16.2 Hz), 3.35 (1H, m), 3.15 (6H,m), 3.03 (1H, m), 2.44 (1H, dt, 14.5, 3.6 Hz), 2.15 (2H, m), 1.80-1.86(4H, m), 1.66 (1H, m), 1.52 (3H, d, 6.3 Hz).

EXAMPLE 61

[0379] Compound 63:

[0380] According to (1-1) described in Example 1, compound 63 wasprepared from radicicol and a hydrochloride of compound u.

[0381] Isomer ratio: about 2:1

[0382] FAB-MS m/z: 521 [M+H]⁺

[0383] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.25 (1H, dd, 16.2, 11.9Hz), 6.72 (1H, d, 16.2 Hz), 6.44 (1H, s), 6.16 (1H, dd, 11.9, 10.6 Hz),5.61 (1H, dd, 10.6, 3.6 Hz), 5.31 (1H, m), 4.24 (2H, m), 3.96 (1H, d,16.2 Hz), 3.89 (1H, m), 3.83 (1H, d, 16.2 Hz), 3.43 (1H, m), 3.35 (1H,m), 2.96-3.10 (5H, m), 2.43 (1H, dt, 10.9, 3.6 Hz), 1.95-2.20 (4H, m),1.75-1.80 (4H, m), 1.62 (1H, m), 1.52 (3H, d, 6.6 Hz).

EXAMPLE 62

[0384] Compound 64:

[0385] According to (1-1) described in Example 1, compound 64 wasprepared from radicicol and a hydrochloride of compound v.

[0386] Isomer ratio: about 3:1

[0387] FAB-MS m/z: 521 [M+H]⁺

[0388] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.24 (1H, dd, 16.2, 11.9Hz), 6.73 (1H, d, 16.2 Hz), 6.42 (1H, s), 6.15 (1H, m), 5.60 (1H, dd,10.8, 4.0 Hz), 5.30 (1H, m), 4.17 (2H, m), 3.92 (1H, d, 16.2 Hz), 3.80(1H, d, 16.2 Hz), 3.70 (2H, m), 3.35 (1H, m), 3.27 (4H, m), 3.02 (1H,ddd, 8.9, 3.3, 2.0 Hz), 2.41-2.56 (7H, m), 1.70 (5H, m), 1.53 (3H, d,6.6 Hz).

EXAMPLE 63

[0389] Compound 65:

[0390] According to (1-1) in Example 1, compound 65 was prepared fromradicicol and a hydrochloride of compound w.

[0391] Isomer ratio: about 4:1

[0392] FAB-MS m/z: 520 [M+H]⁺

[0393] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.24 (1H, dd, 16.2, 11.2Hz), 6.71 (1H, d, 16.2 Hz), 6.42 (1H, s), 6.15 (1H, dd, 10.9, 9.6 Hz),5.60 (1H, dd, 10.9, 3.3 Hz), 5.31 (1H, m), 4.18 (2H, dt, 4.3, 2.0 Hz),3.93 (1H, d, 15.8 Hz), 3.83 (1H, d, 15.8 Hz), 3.35 (1H, m), 3.02 (1H,dd, 8.9, 2.3 Hz), 2.45-2.60 (10H, m), 2.45 (1H, dt, 14.5, 3.6 Hz), 2.36(3H, s), 1.92 (2H, m), 1.62 (1H, m), 1.53 (3H, d, 6.6 Hz).

EXAMPLE 64

[0394] Compound 66:

[0395] According to (1-1) described in Example 1, compound 66 wasprepared from radicicol and a hydrochloride of compound x.

[0396] Isomer ratio: about 1.5:1

[0397] FAB-MS m/z: 596 [M+H]⁺

[0398] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.20-7.30 (3H, m), 6.95(2H, d, 7.9 Hz), 6.84 (1H, t, 7.4 Hz), 6.74 (1H, d, 16.2 Hz), 6.43 (1H,s), 6.11 (1H, m), 5.59 (1H, dd, 10.6, 3.3 Hz), 5.30 (1H, m), 4.20 (2H,m), 3.95 (1H, d, 15.8 Hz), 3.84 (1H, d, 15.8 Hz), 3.34 (1H, m), 3.19(4H, m), 3.01 (1H, dd, 5.6, 3.3 Hz), 2.71 (4H, m), 2.52 (2H, m), 2.40(1H, dd, 14.5, 3.6 Hz), 1.74 (4H, m), 1.61 (1H, m), 1.51 (3H, d, 6.6 Hz)

EXAMPLE 65

[0399] Compound 67:

[0400] According to (1-1) described in Example 1, compound 67 wasprepared from radicicol and a hydrochloride of compound y.

[0401] Isomer ratio: about 2:1

[0402] FAB-MS m/z: 537 [M+H]⁺

[0403] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.24 (1H, dd, 16.2, 11.2Hz), 6.73 (1H, d, 16.2 Hz), 6.42 (1H, s), 6.15 (1H, dd, 10.9, 9.6 Hz),5.59 (1H, dd, 10.9, 3.3 Hz), 5.30 (1H, m), 4.11-4.19 (2H, m), 3.94 (1H,d, 16.2 Hz), 3.84 (1H, d, 16.2 Hz), 3.34 (1H, m), 3.00 (1H, m), 2.78(4H, m), 2.67 (4H, m), 2.47 (3H, m), 1.67 (5H, m), 1.53 (3H, d, 6.6 Hz).

EXAMPLE 66

[0404] Compounds 68 and 69:

[0405] According to (1-1) described in Example 1, a mixture of compounds68 and 69 was prepared from radicicol and a hydrochloride of compound z,and then compounds 68 and 69 were prepared by purifying the mixtureusing high performance liquid chromatography (eluent: 50 mM phosphatebuffer (pH 5.9)/acetonitrile=68/32) according to Example 51.

[0406] Compound 68: FAB-MS m/z: 491 [M+H]⁺

[0407]¹H-NMR (CDCl₃) δ (ppm): 10.08 (1H, br s), 7.18 (1H, dd, 15.5, 11.5Hz), 6.85 (1H, br s), 6.63 (1H, d, 15.5 Hz), 6.60 (1B, s), 6.15 (1H, t,11.5 Hz), 5.67 (1H, d, 11.5 Hz), 5.51 (1H, m), 4.73 (1H, br), 4.29 (2H,t, 5.3 Hz), 4.03 (1H, br), 3.64 (2H, m), 3.51 (3H, m), 3.20 (1H, s),2.98 (1H, m), 2.40 (2H, m), 2.33 (1H, m), 2.01 (2H, m), 1.57 (3H, d, 6.9Hz).

[0408] Compound 69: FAB-MS m/z: 491 [M+H]⁺

[0409]¹H-NMR (CDCl₃) δ (ppm): 11.25 (1H, br s), 7.02 (1H, dd, 16.0, 11.2Hz), 6.58 (1H, br s), 6.11 (1H, d, 16.0 Hz), 6.09 (1H, m), 5.57 (1H, d,10.9 Hz), 5.51 (1H, m), 4.45 (1H, d, 16.5 Hz), 4.34 (2H, d, 5.2 Hz),4.25 (1H, d, 16.5 Hz), 3.80 (1H, m), 3.58 (3H, m), 3.08 (1H, s), 2.91(1H, d, 9.9 Hz), 2.45 (2H, m), 2.32 (1H, m), 2.06 (2H, m), 1.95 (1H, m),1.56 (3H, d, 6.9 Hz).

EXAMPLE 67

[0410] Compound 70:

[0411] According to Example 50, compound 70 was prepared from radicicoland compound aa.

[0412] Isomer ratio: about 2:1

[0413] FAB-MS m/z: 505 [M+H]⁺

[0414] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.25 (1H, dd, 16.2, 11.8Hz), 6.75 (1H, d, 16.2 Hz) 6.43 (1H, s), 6.17 (1H, t, 11.2 Hz), 5.60(1H, dd, 10.6, 3.6 Hz), 5.30 (1H, m), 4.18 (2H, m), 3.92 (1H, d, 16.2Hz), 3.79 (1H, d, 16.2 Hz), 3.49 (2H, m), 3.41 (2H, q, 6.9 Hz), 3.34(1H, m), 3.02 (1H, m), 2.43 (1H, m), 2.37 (2H, m), 2.04 (2H, m), 1.98(2H, m), 1.62 (1H, m), 1.53 (3H, d, 6.6 Hz).

EXAMPLE 68

[0415] Compound 71:

[0416] According to (1-1) described in Example 1, compound 71 wasprepared from radicicol and a trifluoroacetate of compound bb.

[0417] Isomer ratio: about 3:1

[0418] FAB-MS m/z: 507 [M+H]⁺

[0419] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.24 (1H, dd, 16.5, 11.2Hz), 6.77 (1H, d, 16.2 Hz), 6.45 (1H, s), 6.17 (1H, dd, 10.9, 9.6 Hz),5.61 (1H, m), 5.29 (1H, m), 4.11-4.90 (3H, m), 3.99 (1H, d, 16.2 Hz),3.81 (1H, d, 16.2 Hz), 3.39 (4H, m), 3.31 (1H, m), 3.01 (1H, m), 2.43(1H, dt, 14.5, 3.6 Hz), 2.07 (4H, m), 1.60 (1H, m), 1.51 (3H, d, 6.6Hz).

EXAMPLE 69

[0420] Compound 72:

[0421] According to Example 50, compound 72 was prepared from radicicoland compound cc.

[0422] Isomer ratio: about 2:1

[0423] FAB-MS m/z: 580 [M+H]⁺

[0424] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.24 (1H, dd, 16.2, 11.2Hz), 6.72 (1H, d, 16.2 Hz), 6.43 (1H, s), 6.11 (1H, dd, 11.9, 10.6 Hz),5.59 (1H, dd, 10.6, 3.3 Hz), 5.31 (1H, m), 4.99 (1H, t, 5.0 Hz),3.81-3.99 (6H, m), 3.35 (1H, m), 2.99 (1H, m), 2.42 (1H, dt, 14.5, 3.5Hz), 2.03 (2H, m), 1.61 (1H, ddd, 14.2, 4.6, 4.6 Hz), 1.53 (3H, d, 6.3Hz).

EXAMPLE 70

[0425] Compound 73:

[0426] (70-1):

[0427] A 300 mg (0.493 mmol) portion of compound (L) was dissolved in 5ml of dichloromethane to which were subsequently added 0.05 ml (0.493mmol) of ethyl chloroformate and 0.07 ml (0.493 mmol) of triethylamineat −78° C., and the mixture was stirred at 0° C. for 2 hours. Thereaction solution was mixed with a saturated ammonium chloride aqueoussolution and extracted with ethyl acetate. The ethyl acetate layer waswashed with saturated brine and dried with anhydrous sodium sulfate, andthen the solvent was evaporated under reduced pressure. The resultingresidue was purified by silica gel column chromatography (n-hexane/ethylacetate=6/1) to obtain 188 mg (yield, 56%) of adi-tert-butyldimethylsilyl derivative of compound 73.

[0428] (70-2):

[0429] According to (55-4) described in Example 55, compound 73 wasprepared from the di-tert-butyldimethylsilyl derivative of compound 73.

[0430] Isomer ratio: about 1.3:1

[0431] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.45 (1H, dd, 16.3, 11.4Hz), 6.71 (1H, d, 15.8 Hz), 6.46 (1H, s), 6.22 (1H, m), 5.73 (1H, dd,10.4, 3.0 Hz), 5.33 (1H, m), 4.34 (1H, d, 6.9 Hz), 4.11 (1H, d, 16.3Hz), 4.00 (1H, d, 16.3 Hz), 3.35 (1H, m), 3.04 (1H, m), 2.43 (1H, dt,14.3, 3.5 Hz), 1.61 (1H, m), 1.53 (3H, d, 6.4 Hz), 1.35 (3H, t, 6.9 Hz).

EXAMPLE 71

[0432] Compound 74:

[0433] According to (70-1) and (70-2) described in Example 70, compound74 was prepared from compound (L), triethylamine and methyl isocyanate.

[0434] Isomer ratio: about 1.2:1

[0435] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.42 (1H, dd, 16.3, 11.9Hz), 6.76 (1H, d, 16.3 Hz), 6.46 (1H, s), 6.26 (1H, dd, 11.9, 10.6 Hz),5.71 (1H, dd, 10.9, 3.5 Hz), 5.34 (1H, m), 4.10 (1H, d, 16.3 Hz), 3.85(1H, d, 16.3 Hz), 3.36 (1H, m), 3.04 (1H, m), 2.85 (3H, s), 2.43 (1H,dt, 14.3, 3.5 Hz), 1.65 (1H, m), 1.53 (3H, d, 6.4 Hz).

EXAMPLE 72

[0436] Compound 75:

[0437] According to (70-1) and (70-2) described in Example 70, compound75 was prepared from compound (L), triethylamine and acetyl chloride.

[0438] Isomer ratio: about 1.2:1

[0439] Major component: ¹H-NMR (CD₃OD) δ (ppm): 7.43 (1H, dd, 15.8, 11.9Hz), 6.75 (1H, d, 15.8 Hz), 6.47 (1H, s), 6.15 (1H, dd, 11.9, 10.6 Hz),5.72 (1H, dd, 10.4, 3.5 Hz), 5.34 (1H, m), 4.13 (1H, d, 16.3 Hz), 4.04(1H, d, 16.3 Hz), 3.35 (1H, m), 3.04 (1H, m), 2.40 (1H, dt, 14.3, 3.5Hz), 2.23 (3H, s), 1.65 (1H, m), 1.53 (3H, d, 6.9 Hz).

EXAMPLE 73

[0440] Compound 76:

[0441] According to (1-1) described in Example 1, compound 76 wasprepared from radicicol and O-phenylhydroxylamine hydrochloride.

[0442] Isomer ratio: about 3:1

[0443] FAB-MS m/z: 456 [M+H]⁺

[0444] Major component: ¹H-NMR (CDCl₃) δ (ppm): 10.95 (1H, br),7.24-7.38 (5H, m), 7.05 (1H, m), 6.89 (1H, d, 16.2 Hz), 6.61 (1H, s),6.23 (1H, ddd, 10.2, 10.2, 1.1 Hz), 5.73 (1H, br d, 10.2 Hz), 5.53 (1H,m), 4.85 (1H, br), 4.21 (1H, br), 3.23 (1H, br), 3.01 (1H, ddd, 8.3,2.6, 2.3 Hz), 2.37 (1H, ddd, 15.2, 3.6, 3.3 Hz), 2.01 (1H, ddd, 15.5,9.1, 3.8 Hz), 1.58 (3H, d, 6.6 Hz).

REFERENCE EXAMPLE 1

[0445] Compound a:

[0446] (1-1):

[0447] A 5.00 g (22.4 mmol) portion of 8-bromooctanoic acid wasdissolved in a mixed solvent of 2 ml dichloromethane and 10 ml hexane,and the solution was mixed with 8.00 ml (44.8 mmol) of tert-butyl2,2,2-trichloroacetoimidate and 0.45 ml (3.66 mmol) of borontrifluoride-ether complex and stirred at room temperature for 1 hour.The reaction solution was mixed with 10 ml of hexane and 0.031 g (3.66mmol) of sodium bicarbonate, the resulting precipitate was separated byfiltration, and then the solvent was evaporated under reduced pressure.The resulting residue was purified by silica gel column chromatography(n-hexane/ethyl acetate=5/1) to obtain 2.34 g (yield, 38%) of tert-butyl8-bromooctanoate.

[0448] (1-2):

[0449] A 2.70 g (8.29 mmol) portion of tert-butyl 8-bromooctanoate wasdissolved in 20 ml of DMF, and the solution was mixed with 1.35 g (8.28mmol) N-hydroxyphthalimide and 1.86 ml (12.4 mmol) of1,8-diazabicyclo[5,4,0]-7-undecene and stirred at room temperature for20.5 hours. The reaction solution was mixed with water and extractedwith ethyl acetate, the ethyl acetate layer was washed with 0.5 Nhydrochloric acid and then with saturated brine and dried with anhydroussodium sulfate, subsequently evaporating the solvent under reducedpressure. The resulting residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate=5/1) to obtain 0.83 g (yield,28%) of tert-butyl 8-(phthalimidoxy)-octanoate.

[0450]¹H-NMR (CDCl₃) δ (ppm): 7.83 (2H, m), 7.75 (2H, m), 4.20 (2H, t,6.8 Hz), 2.21 (2H, t, 7.6 Hz), 1.79 (2H, m), 1.60 (2H, m), 1.44 (9H, s),1.45-1.29 (6H, m).

[0451] (1-3):

[0452] A 1.00 g (2.77 mmol) portion of tert-butyl8-(phthalimidoxy)-octanoate was dissolved in 9 ml of chloroform, and thesolution was mixed with 4.1 ml (4.16 mmol) of a 1 M hydrazinemonohydrate/methanol solution and stirred at room temperature for 0.5hour. After separation of the resulting precipitate by filtration, theresulting filtrate was mixed with water and extracted with chloroform,the chloroform layer was washed with saturated brine and dried withanhydrous sodium sulfate, and then the solvent was evaporated underreduced pressure. The thus prepared residue was dissolved in 14 ml ofdichloromethane, and the solution was mixed with 6.4 ml oftrifluoroacetic acid and stirred at room temperature for 2 hours. Byevaporating the solvent under reduced pressure, a trifluoroacetate ofthe compound a was prepared.

REFERENCE EXAMPLE 2

[0453] Compound b:

[0454] According to (1-1) to (1-3) described in Reference Example 1, atrifluoroacetate of compound b was prepared from 11-bromoundecanoicacid.

REFERENCE EXAMPLE 3

[0455] Compound c:

[0456] (3-1):

[0457] According to (1-2) described in Reference Example 1, 1.29 g(quantitative) of methyl 2-methoxymethoxybenzoate was prepared from 1.00g (6.57 mmol) of methyl salicylate, 0.75 ml (9.86 mmol) of chloromethylmethyl ether and 1.72 ml (9.86 mmol) of diisopropylethylamine.

[0458] (3-2):

[0459] A 792 mg (4.04 mmol) portion of methyl 2-methoxymethoxybenzoatedissolved in 12 ml of THF was added to 337 mg (8.89 mmol) of lithiumaluminum hydride dissolved in 5 ml of THF, and the mixture was stirredat room temperature for 2.5 hours. The reaction solution was mixed withwater and extracted with ethyl acetate, and the ethyl acetate layer waswashed with saturated brine and dried with anhydrous sodium sulfate. Byevaporation of the solvent under reduced pressure, 640 mg (yield, 94%)of 2-methoxymethoxybenzyl alcohol was prepared.

[0460] (3-3):

[0461] According to (55-3) described in Example 55, 486 mg (yield, 57%)of N-(2-methoxymethoxybenzyloxy)phthalimide was prepared from 454 mg(2.70 mmol) of 2-methoxymethoxybenzyl alcohol, 484 mg (2.97 mmol) ofN-hydroxyphthalimide, 744 mg (2.84 mmol) of triphenylphosphine and 0.446ml (2.84 mmol) of DEAD.

[0462] (3-4):

[0463] According to (1-3) described in Reference Example 1, a reactionsolution prepared by treating 427 mg (1.36 mmol) ofN-(2-methoxymethoxybenzyloxy)phthalimide with 0.099 ml (2.04 mmol) ofhydrazine monohydrate was separated by filtration, and then the solventwas evaporated under reduced pressure to obtain 244 mg (yield, 98%) ofcompound c.

[0464] FAB-MS m/z: 184 [M+H]⁺

[0465]¹H-NMR (CDCl₃) δ (ppm): 7.37 (1H, dd, 7.4, 1.8 Hz), 7.27 (1H, ddd,7.4, 7.3, 1.8 Hz), 7.11 (1H, dd, 7.3, 1.3 Hz), 7.02 (1H, ddd, 7.6, 7.6,1.3 Hz), 5.42 (2H, br s), 5.22 (2H, s), 4.79 (2H, s), 3.49 (3H, s).

REFERENCE EXAMPLE 4

[0466] Compound d:

[0467] According to (55-1) described in Example 55, methyl3,5-di-(tert-butyldimethylsiloxy)benzoate was prepared from methyl3,5-dihydroxybenzoate, and compound d was prepared from methyl3,5-di-(tert-butyldimethylsiloxy) benzoate according to (3-2) to (3-4)described in Reference Example 3.

[0468] FAB-MS m/z: 384 [M+H]⁺

[0469]¹H-NMR (CDCl₃) δ (ppm): 6.46 (2H, d, 2.3 Hz), 6.28 (1H, t, 2.3Hz), 5.37 (2H, br), 4.57 (2H, s), 0.97 (18H, s), 0.19 (12H, s).

REFERENCE EXAMPLE 5

[0470] Compound e:

[0471] According to (3-2) to (3-4) described in Reference Example 3,compound e was prepared from methyl 3,4,5-trimethoxybenzoate.

[0472] FAB-MS m/z: 214 [M+H]⁺

[0473]¹H-NMR (CDCl₃) δ (ppm): 6.60 (2H, s), 5.43 (2H, br), 4.64 (2H, s),3.88 (6H, s), 3.85 (3H, s).

REFERENCE EXAMPLE 6

[0474] Compound f:

[0475] (6-1):

[0476] A 2.00 g (13.1 mmol) portion of 3,5-diaminobenzoic acid wasdissolved in a mixed solvent of 20 ml THF and 20 ml water, and thesolution was mixed with 6.88 g (31.5 mmol) of di-tert-butyl dicarbonate,adjusted to pH 7 to 8 with a saturated sodium bicarbonate aqueoussolution and then stirred at room temperature for 4 hours. The reactionsolution was mixed with a 10% citric acid aqueous solution and extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine and dried with anhydrous sodium sulfate, and then the solvent wasevaporated under reduced pressure. The resulting residue was purified bysilica gel column chromatography (chloroform/methanol=10/1) to obtain3.93 g (yield, 85%) of 3,5-di-(tert-butoxycarbonylamino)benzoic acid.

[0477] (6-2):

[0478] A 2.00 g (5.68 mmol) portion of3,5-di-(tert-butoxycarbonylamino)benzoic acid was dissolved in 15 ml ofTHF, 3.77 ml (39.7 mmol) of borane-methyl sulfide complex dissolved in10 ml of THF was added dropwise to the thus prepared solution, and themixture was stirred at room temperature for 5 hours. The reactionsolution was cooled to 0° C., mixed with water and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine anddried with anhydrous sodium sulfate, and then the solvent was evaporatedunder reduced pressure. The resulting residue was purified by silica gelcolumn chromatography (chloroform/methanol=20/1) to obtain 1.08 g(yield, 56%) of 1,3-di-tert-butoxycarbonylamino-5-hydroxymethylbenzene.

[0479] (6-3):

[0480] According to (3-3) and (3-4) described in Reference Example 3,compound f was prepared from1,3-di-tert-butoxycarbonylamino-5-hydroxymethylbenzene.

[0481] FAB-MS m/z: 354 [M+H]⁺

[0482]¹H-NMR (CDCl₃) δ (ppm): 7.41 (1H, t, 1.7 Hz), 7.07 (2H, d, 1.7Hz), 6.50 (2H, br s), 5.39 (2H, br), 4.62 (2H, s), 1.50 (18H, s).

REFERENCE EXAMPLE 7

[0483] Compound g:

[0484] According to (3-3) and (3-4) described in Reference Example 3,compound g was prepared from 4-(dimethylamino)phenetyl alcohol.

[0485] FAB-MS m/z: 181 [M+H]⁺

[0486]¹H-NMR (CDCl₃) δ (ppm): 7.10 (2H, d, 8.6 Hz), 6.70 (2H, d, 8.6Hz), 5.38 (2H, br s), 3.84 (2H, t, 7.1 Hz), 2.91 (6H, s), 2.81 (2H, t,7.1 Hz).

REFERENCE EXAMPLE 8

[0487] Compound h:

[0488] According to (6-2) and (6-3) described in Reference Example 6,compound h was prepared from 4-(N-methylpiperazinomethyl)benzoic acid.

[0489]¹H-NMR (CDCl₃) δ (ppm): 7.29 (2H, m), 7.15 (2H, m), 5.20 (2H, br),4.56 (2H, s), 3.93 (2H, s), 3.44-3.41 (4H, br), 2.68-2.58 (4H, m), 2.55(3H, s).

REFERENCE EXAMPLE 9

[0490] Compound i:

[0491] According to (1-2) described in Reference Example 1, methyl2-(dimethylaminosulfonyl)benzoate was prepared from methyl2-(aminosulfonyl)benzoate, methyl iodide and potassium carbonate, andthen compound i was prepared according to (3-2) to (3-4) described inReference Example 3.

[0492] FAB-MS m/z: 231 [M+H]⁺

[0493]¹H-NMR (CDCl₃+CD₃OD) δ (ppm): 7.87 (1H, d, 7.9 Hz), 7.71 (1H, d,7.6 Hz), 7.62 (1H, dd, 7.9, 7.3 Hz), 7.46 (1H, dd, 7.6, 7.3 Hz), 5.10(2H, s), 2.81 (6H, s).

REFERENCE EXAMPLE 10

[0494] Compound j:

[0495] According to (3-3) and (3-4) described in Reference Example 3,compound j was prepared from 2-pyridylcarbinol.

[0496]¹H-NMR (CDCl₃) δ (ppm): 7.21-7.30 (5H, m), 5.40 (2H, br), 3.90(2H, t, 6.9 Hz), 2.91 (2H, t, 6.9 Hz).

REFERENCE EXAMPLE 11

[0497] Compound k:

[0498] According to (3-3) and (3-4) described in Reference Example 3,compound k was prepared from 3-pyridylcarbinol. ¹H-NMR (CDCl₃) δ (ppm):8.63 (1H, d, 2.0 Hz), 8.57 (1H, dd, 5.0, 1.5 Hz), 7.73 (1H, dt, 7.9, 2.0Hz), 7.33 (1H, dd, 7.9, 4.9 Hz), 4.92 (2H, br), 4.71 (2H, s).

REFERENCE EXAMPLE 12

[0499] Compound m:

[0500] According to (3-3) and (3-4) described in Reference Example 3,compound m was prepared from 4-pyridylcarbinol. ¹H-NMR (CDCl₃) δ (ppm):8.59 (2H, d, 5.9 Hz), 7.26 (2H, d, 5.9 Hz), 5.55 (2H, br), 4.71 (2H, s).

REFERENCE EXAMPLE 13

[0501] Compound n:

[0502] According to (3-3) and (3-4) described in Reference Example 3,compound n was prepared from 3-pyridinepropanol. ¹H-NMR (CDCl₃) δ (ppm):8.45 (1H, br s), 8.43 (1H, dd, 4.9, 1.3 Hz), 7.50 (1H, ddd, 7.6, 1.6,1.3 Hz), 7.20 (1H, dd, 7.6, 4.9 Hz), 5.36 (2H, br), 3.67 (2H, t, 6.3Hz), 2.67 (2H, t, 7.8 Hz), 1.90 (2H, m).

REFERENCE EXAMPLE 14

[0503] Compound o:

[0504] According to (3-1) to (3-4) described in Reference Example 3,compound o was prepared from 3-hydroxypicolinic acid.

[0505] FAB-MS m/z: 185 [M+H]⁺

[0506]¹H-NMR (CDCl₃) δ (ppm): 8.27 (1H, dd, 4.6, 1.3 Hz), 7.42 (1H, dd,8.3, 1.3 Hz), 7.18 (1H, dd, 8.3, 4.6 Hz), 5.75 (2H, br), 5.22 (2H, d,0.7 Hz), 4.92 (2H, s), 3.47 (3H, d, 1.0 Hz).

REFERENCE EXAMPLE 15

[0507] Compound p:

[0508] According to (3-1) to (3-4) described in Reference Example 3,compound p was prepared from 6-hydroxynicotinic acid.

[0509]¹H-NMR (CDCl₃+CD₃OD) δ (ppm): 7.98 (1H, d, 2.3 Hz), 7.52 (1H, dd,8.6, 2.3 Hz), 6.68 (1H, d, 8.2 Hz), 5.32 (2H, s), 4.46 (2H, s), 3.35(3H, s).

REFERENCE EXAMPLE 16

[0510] Compound q:

[0511] (16-1):

[0512] According to (1-2) described in Reference Example 1, tert-butylN-(6-uracilmethoxy)carbamate was prepared from tert-butylN-hydroxycarbamate, sodium hydride, and 6-(chloromethyl)uracil.

[0513] FAB-MS m/z: 258 [M+H]⁺

[0514]¹H-NMR (CDCl₃) δ (ppm): 10.34 (1H, br), 8.02 (1H, br), 5.54 (1H,s), 4.67 (2H, s), 1.48 (9H, s).

[0515] (16-2):

[0516] A 385 mg (1.50 mmol) portion of tert-butylN-(6-uracilmethoxy)carbamate was dissolved in 0.5 ml of dichloromethane,and the solution was mixed with 0.5 ml of trifluoroacetic acid andstirred at room temperature for 1 hour. By evaporating the solvent underreduced pressure, a trifluoroacetate of compound q was prepared.

REFERENCE EXAMPLE 17

[0517] Compound r:

[0518] According to (3-3) and (3-4) described in Reference Example 3,compound r was prepared from 1-methyl-3-piperidinemethanol.

[0519]¹H-NMR (CDCl₃) δ (ppm): 5.47 (2H, br), 3.55 (1H, dd, 9.9, 5.6 Hz),3.48 (1H, dd, 9.9, 7.6 Hz), 2.92 (1H, br d, 10.9 Hz), 2.81 (1H, br d,11.2 Hz), 2.28 (3H, s), 2.03 (1H, m), 1.89-1.97 (2H, m), 1.59-1.71 (4H,m).

REFERENCE EXAMPLE 18

[0520] Compound s:

[0521] According to (3-3) described in Reference Example 3,1-(2-phthalimidoxyethyl)pyrrolidine was prepared from pyrrolidineethanoland treated with a 4 N hydrochloric acid/ethyl acetate solution to makeit into a hydrochloride, and then compound s was prepared from thehydrochloride according to (3-4) described in Reference Example 3. Bytreating compound s with a 4 N hydrochloric acid/ethyl acetate solution,a hydrochloride of compound s was prepared.

[0522] FAB-MS m/z: 145 [M+H]⁺

REFERENCE EXAMPLE 19

[0523] Compound t:

[0524] (19-1):

[0525] According to (1-2) described in Reference Example 1, 4.20 g(yield, 39%) of ethyl N-(3-bromopropoxy)acetoimidate was prepared from5.00 g (48.5 mmol) of ethyl acetohydroxamate, 1.90 g (48.5 mmol) ofsodium hydride and 7.4 ml (72.7 mmol) of 1,3-dibromopropane.

[0526] (19-2):

[0527] A 500 mg (2.23 mmol) portion of ethylN-(3-bromopropoxy)acetoimidate was dissolved in 6 ml of dichloromethane,and the solution was mixed with 0.22 ml (2.23 mmol) of piperidine and0.33 ml (2.23 mmol) of 1,8-diazabicyclo(5.4,0]-7-undecene and stirred atroom temperature for 36 hours. The reaction solution was mixed with asaturated ammonium chloride aqueous solution and extracted withchloroform. The chloroform layer was washed with saturated brine anddried with anhydrous sodium sulfate, and then the solvent was evaporatedunder reduced pressure. The resulting residue was purified by silica gelchromatography (chloroform/methanol=10/1) to obtain 166 mg (yield, 32%)of ethyl N-(3-piperidinopropoxy)acetoimidate.

[0528] FAB-MS m/z: 229 [M+H]⁺

[0529]¹H-NMR (CDCl₃) δ (ppm): 4.00 (2H, q, 6.9 Hz), 3.93 (2H, t, 6.3Hz), 2.53 (6H, m), 1.93 (2H, m), 1.92 (3H, s), 1.70 (4H, m), 1.49 (2H,m), 1.27 (3H, t, 6.9 Hz).

[0530] (19-3):

[0531] A 166 mg (0.71 mmol) portion of ethylN-(3-piperidinopropoxy)acetoimidate was dissolved in 0.5 ml of THF, andthe solution was mixed with 0.1 ml of concentrated hydrochloric acid andstirred at room temperature for 1 hour. By evaporating the solvent underreduced pressure, a hydrochloride of compound t was prepared.

REFERENCE EXAMPLE 20

[0532] Compound u:

[0533] According to (19-2) and (19-3) described in Reference Example 19,a hydrochloride of compound u was prepared from ethylN-(3-bromopropoxy)acetoimidate.

REFERENCE EXAMPLE 21

[0534] Compound v:

[0535] According to (19-1) described in Reference Example 19, ethylN-(4-bromobutoxy)acetoimidate was prepared from ethyl acetohydroxamate,sodium hydride and 1,4-dibromobutane, and then a hydrochloride ofcompound v was prepared according to (19-2) and (19-3) described inReference Example 19.

REFERENCE EXAMPLE 22

[0536] Compound w:

[0537] According to (19-2) and (19-3) described in Reference Example 19,a hydrochloride of compound w was prepared from ethylN-(3-bromopropoxy)acetoimidate.

REFERENCE EXAMPLE 23

[0538] Compound x:

[0539] According to (19-2) and (19-3) described in Reference Example 19,a hydrochloride of compound x was prepared from ethylN-(4-bromobutoxy)acetoimidate.

REFERENCE EXAMPLE 24

[0540] Compound y:

[0541] According to (19-2) and (19-3) described in Reference Example 19,a hydrochloride of compound y was prepared from ethylN-(4-bromobutoxy)acetoimidate.

REFERENCE EXAMPLE 25

[0542] Compound z:

[0543] According to (3-3) and (3-4) described in Reference Example 3,compound z was prepared from 1-(2-hydroxyethyl)-2pyrrolidinone, and thencompound z was treated with a 4 N hydrochloric acid/ethyl acetatesolution to obtain a hydrochloride of compound z.

[0544] FAB-MS m/z: 145 [M+H]⁺

REFERENCE EXAMPLE 26

[0545] Compound aa:

[0546] According to (3-3) and (3-4) described in Reference Example 3,compound aa was prepared from 1-(3-hydroxypropyl)-2-pyrrolidinone.

[0547]¹H-NMR (CDCl₃) δ (ppm): 5.40 (2H, br), 3.68 (2H, t, 6.3 Hz), 3.39(2H, dd, 11.5, 6.9 Hz), 3.37 (2H, m), 2.39 ( 2H, dd, 8.6, 7.6 Hz), 2.02(2H, ddd, 6.9, 6.3, 1.0 Hz), 1.81 (2H, ddd, 11.5, 6.3, 1.0 Hz), 1.81(2H, m).

REFERENCE EXAMPLE 27

[0548] Compound bb:

[0549] (27-1):

[0550] According to (16-1) described in Reference Example 16, 659 mg(3.80 mmol) of tert-butyl N-(allyloxy)carbamate prepared from tert-butylN-hydroxycarbamate, sodium hydride and allyl bromide was dissolved in 10ml of dichloromethane, and the thus prepared solution was mixed with 886mg (4.67 mmol) of m-chloroperbenzoic acid and stirred at roomtemperature for 24 hours. The reaction solution was filtered, mixed witha 1 N sodium hydroxide aqueous solution and extracted with chloroform.The chloroform layer was washed with saturated brine and dried withanhydrous sodium sulfate, and then the solvent was evaporated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (n-hexane/ethyl acetate=4/1) to obtain 447 mg(yield, 62%) of tert-butyl N-(2,3-epoxypropoxy)carbamate.

[0551] (27-2):

[0552] A 150 mg (0.79 mmol) portion of tert-butylN-(2,3-epoxypropoxy)carbamate was dissolved in 1 ml of methanol, and thesolution was mixed with 0.08 ml (0.95 mmol) of pyrrolidine and stirredat room temperature for 14 hours. The reaction solution was mixed with asaturated ammonium chloride aqueous solution and extracted withchloroform. The chloroform layer was washed with saturated brine anddried with anhydrous sodium sulfate, and then the solvent was evaporatedunder reduced pressure to obtain 181 mg (yield, 88%) of tert-butylN-(2-hydroxy-3-pyrrolidinylpropoxy)-carbamate.

[0553] FAB-MS m/z: 261 [M+H]⁺

[0554]¹H-NMR (CDCl₃) δ (ppm): 4.02 (1H, m), 3.92 (1H, dd, 11.2, 3.3 Hz),3.77 (1H, dd, 11.2, 7.3 Hz), 2.68 (4H, m), 2.65 (1H, m), 2.50 (1H, m),1.89 (9H, s), 1.80 (4H, m).

[0555] (27-3):

[0556] According to (16-2) described in Reference Example 16, atrifluoroacetate of compound bb was prepared from tertbutylN-(2-hydroxy-3-pyrrolidinylpropoxy)carbamate.

REFERENCE EXAMPLE 28

[0557] Compound cc:

[0558] According to (1-2) described in Reference Example 1,2-(2-phthalimidoxyethyl)-1,3-dioxolan was prepared from2-(2-bromoethyl)-1,3-dioxolan, N-hydroxyphthalimide and potassiumcarbonate, and then compound cc was prepared from2-(2-phthalimidoxyethyl)-1,3-dioxolan according to (3-4) described inReference Example 3.

[0559]¹H-NMR (CDCl₃) δ (ppm): 5.40 (2H, br), 4.97 (1H, t, 5.0 Hz),3.80-4.00 (6H, m), 1.98 (2H, dt, 6.3, 5.0 Hz). TABLE 6 Reference ExampleH₂NO—R^(3e) Compound R^(3e) a (CH₂)₇CO₂H b (CH₂)₁₀CO₂H c

d

e

f

g

h

i

j

k

m

n

o

p

q

r

s

t

u

v

w

x

y

z

aa

bb

cc

[0560] Industrial Applicability

[0561] According to the present invention, novel radicicol derivativesor pharmacologically acceptable salts thereof which show tyrosine kinaseinhibition activity and have antitumor or immunosuppression effects areprovided.

What is claimed is:
 1. A radicicol derivative represented by thefollowing formula (I) or a pharmacologically acceptable salt thereof:

wherein R¹ and R² are the same or different, and each representshydrogen, alkanoyl, alkenoyl, tert-butyldiphenylsilyl ortert-butyldimethylsilyl; R³ represents: Y—R⁵ {wherein Y representssubstituted or unsubstituted alkylene; and R⁵ represents CONR⁶R⁷(wherein R⁶ represents hydrogen, hydroxyl, substituted or unsubstitutedlower alkyl, substituted or unsubstituted higher alkyl, substituted orunsubstituted lower cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted lower alkoxy, substituted or unsubstitutedaryl, a substituted or unsubstituted heterocyclic group, or NR⁸R⁹(wherein R⁸ and R⁹ are the same or different, and each representshydrogen, substituted or unsubstituted lower alkyl, substituted orunsubstituted higher alkyl, substituted or unsubstituted lowercycloalkyl, substituted or unsubstituted aryl, a substituted orunsubstituted heterocyclic group, substituted or unsubstituted alkanoyl,substituted or unsubstituted aroyl, carbonyl bound to a substituted orunsubstituted heterocyclic ring, or substituted or unsubstitutedarylcarbamoyl), or is combined together with R⁷ and adjoining N torepresent a substituted or unsubstituted heterocyclic group; and R⁷ iscombined together with R⁶ and adjoining N to represent a substituted orunsubstituted heterocyclic group, or represents hydroxyl, substitutedlower alkyl, substituted or unsubstituted higher alkyl, substituted orunsubstituted lower cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted lower alkoxy, substituted or unsubstitutedaryl, a substituted or unsubstituted heterocyclic group, or NR¹⁰R¹¹(wherein R¹⁰ and R¹¹ have the same meaning as R⁸ and R⁹ defined above,respectively)), CO₂R¹² (wherein R¹² represents substituted lower alkyl,substituted or unsubstituted higher alkyl, substituted or unsubstitutedlower cycloalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted aryl, or a substituted or unsubstituted heterocyclicgroup), substituted or unsubstituted aryl, substituted or unsubstitutedpyridyl, substituted or unsubstituted pyridonyl, substituted orunsubstituted pyrrolidonyl, substituted or unsubstituted uracilyl,substituted or unsubstituted piperidyl, substituted or unsubstitutedpiperidino, substituted or unsubstituted pyrrolidinyl, substituted orunsubstituted morpholino, substituted or unsubstituted morpholinyl,substituted or unsubstituted piperazinyl, substituted or unsubstitutedthiomorpholino, or substituted or unsubstituted dioxolanyl}, COR¹³(wherein R¹³ represents hydrogen, substituted or unsubstituted loweralkyl, substituted or unsubstituted higher alkyl, substituted orunsubstituted aryl, substituted or unsubstituted lower alkoxy, orNR¹⁴R¹⁵ (wherein R¹⁴ and R¹⁵ are the same or different, and eachrepresents hydrogen, substituted or unsubstituted lower alkyl,substituted or unsubstituted higher alkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted pyridyl, or R¹⁴ and R¹⁵ arecombined together with adjoining N to represent a substituted orunsubstituted heterocyclic group)), or substituted or unsubstitutedaryl; X represents halogen, or is combined together with R⁴ to representa single bond; and R⁴ is combined together with X to represent a singlebond, or represents hydrogen, alkanoyl, alkenoyl, or —SO-Z {wherein Zrepresents formula (A):

wherein R^(1A) and R^(2A) have the same meaning as R¹ and R² definedabove, respectively; X^(A) represents halogen; and W represents O orN—O—R^(3A) (wherein R^(3A) has the same meaning as R³ defined above)}.2. The compound according to claim 1 or a pharmacologically acceptablesalt thereof, wherein X is halogen.
 3. The compound according to claim 1or a pharmacologically acceptable salt thereof, wherein X is combinedtogether with R⁴ to represent a single bond.
 4. The compound accordingto claim 3 or a pharmacologically acceptable salt thereof, wherein R¹and R² each is hydrogen.
 5. The compound according to claim 4 or apharmacologically acceptable salt thereof, wherein R³ is Y—R⁵.
 6. Thecompound according to claim 5 or a pharmacologically acceptable saltthereof, wherein R⁵ is substituted or unsubstituted aryl, substituted orunsubstituted pyridyl, substituted or unsubstituted pyridonyl,substituted or unsubstituted pyrrolidonyl, substituted or unsubstituteduracilyl, substituted or unsubstituted piperidyl, substituted orunsubstituted piperidino, substituted or unsubstituted pyrrolidinyl,substituted or unsubstituted morpholino, substituted or unsubstitutedmorpholinyl, substituted or unsubstituted piperazinyl., substituted orunsubstituted thiomorpholino, or substituted or unsubstituteddioxolanyl.
 7. The compound according to claim 5 or a pharmacologicallyacceptable salt thereof, wherein R⁵ is pyrrolidonyl.
 8. A therapeuticagent of diseases caused by tyrosine kinase, which comprises at leastone of the compounds according to any one of claims 1 to 6 or apharmacologically acceptable salt thereof.